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Sample records for pleiotropic regulatory locus

  1. Pleiotropic locus for emotion recognition and amygdala volume identified using univariate and bivariate linkage

    PubMed Central

    Knowles, Emma E. M.; McKay, D. Reese; Kent, Jack W.; Sprooten, Emma; Carless, Melanie A.; Curran, Joanne E.; de Almeida, Marcio A. A.; Dyer, Thomas D.; Göring, Harald H. H.; Olvera, Rene; Duggirala, Ravi; Fox, Peter; Almasy, Laura; Blangero, John; Glahn, David. C.

    2014-01-01

    The role of the amygdala in emotion recognition is well established and separately each trait has been shown to be highly heritable, but the potential role of common genetic influences on both traits has not been explored. Here we present an investigation of the pleiotropic influences of amygdala and emotion recognition in a sample of randomly selected, extended pedigrees (N = 858). Using a combination of univariate and bivariate linkage we found a pleiotropic region for amygdala and emotion recognition on 4q26 (LOD = 4.34). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (pBonferroni = 5.01×10−05) within an intron of PDE5A (rs2622497, Χ2 =16.67, p = 4.4×10−05) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability including the amygdala. The present paper extends our understanding of the shared etiology between amygdala and emotion recognition by showing that the overlap between the two traits is due, at least in part, to common genetic influences. Moreover, the present paper identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5-inhibitors for ameliorating emotion-recognition deficits in populations including, but not exclusively, those individuals suffering from mental or neurodegenerative illness. PMID:25322361

  2. Regulatory organization of the staphylococcal sae locus.

    PubMed

    Adhikari, Rajan P; Novick, Richard P

    2008-03-01

    This paper describes an investigation of the complex internal regulatory circuitry of the staphylococcal sae locus and the impact of modifying this circuitry on the expression of external genes in the sae regulon. The sae locus contains four genes, the saeR and S two-component signalling module (TCS), and saeP and Q, two upstream genes of hitherto unknown function. It is expressed from two promoters, P(A)sae, which transcribes only the TCS, and P(C)sae, which transcribes the entire locus. A bursa aurealis (bursa) transposon insertion in saeP in a derivative of Staphylococcus aureus NCTC 8325 has a profound effect on sae function. It modifies the activity of the TCS, changing the expression of many genes in the sae regulon, even though transcription of the TCS (from P(A)sae) is not interrupted. Moreover, these effects are not due to disruption of saeP since an in-frame deletion in saeP has essentially no phenotype. The phenotype of S. aureus strain Newman is remarkably similar to that of the saeP : : bursa and this similarity is explained by an amino acid substitution in the Newman saeS gene that is predicted to modify profoundly the signalling function of the protein. This concurrence suggests that the saeP : : bursa insertion affects the signalling function of saeS, a suggestion that is supported by the ability of an saeQR clone, but not an saeR clone, to complement the effects of the saeP : : bursa insertion.

  3. Identifying regulatory mechanisms underlying tumorigenesis using locus expression signature analysis.

    PubMed

    Lee, Eunjee; de Ridder, Jeroen; Kool, Jaap; Wessels, Lodewyk F A; Bussemaker, Harmen J

    2014-04-15

    Retroviral insertional mutagenesis is a powerful tool for identifying putative cancer genes in mice. To uncover the regulatory mechanisms by which common insertion loci affect downstream processes, we supplemented genotyping data with genome-wide mRNA expression profiling data for 97 tumors induced by retroviral insertional mutagenesis. We developed locus expression signature analysis, an algorithm to construct and interpret the differential gene expression signature associated with each common insertion locus. Comparing locus expression signatures to promoter affinity profiles allowed us to build a detailed map of transcription factors whose protein-level regulatory activity is modulated by a particular locus. We also predicted a large set of drugs that might mitigate the effect of the insertion on tumorigenesis. Taken together, our results demonstrate the potential of a locus-specific signature approach for identifying mammalian regulatory mechanisms in a cancer context.

  4. Amylase and chitinase genes in Streptomyces lividans are regulated by reg1, a pleiotropic regulatory gene.

    PubMed Central

    Nguyen, J; Francou, F; Virolle, M J; Guérineau, M

    1997-01-01

    A regulatory gene, reg1, was identified in Streptomyces lividans. It encodes a 345-amino-acid protein (Reg1) which contains a helix-turn-helix DNA-binding motif in the N-terminal region. Reg1 exhibits similarity with the LacI/GalR family members over the entire sequence. It displays 95% identity with MalR (the repressor of malE in S. coelicolor), 65% identity with ORF-Sl (a putative regulatory gene of alpha-amylase of S. limosus), and 31% identity with CcpA (the carbon catabolite repressor in Bacillus subtilis). In S. lividans, the chromosomal disruption of reg1 affected the expression of several genes. The production of alpha-amylases of S. lividans and that of the alpha-amylase of S. limosus in S. lividans were enhanced in the reg1 mutant strains and relieved of carbon catabolite repression. As a result, the transcription level of the alpha-amylase of S. limosus was noticeably increased in the reg1 mutant strain. Moreover, the induction of chitinase production in S. lividans was relieved of carbon catabolite repression by glucose in the reg1 mutant strain, while the induction by chitin was lost. Therefore, reg1 can be regarded as a pleiotropic regulatory gene in S. lividans. PMID:9335287

  5. The INO2 and INO4 loci of Saccharomyces cerevisiae are pleiotropic regulatory genes.

    PubMed Central

    Loewy, B S; Henry, S A

    1984-01-01

    We isolated a mutant of Saccharomyces cerevisiae defective in the formation of phosphatidylcholine via methylation of phosphatidylethanolamine. The mutant synthesized phosphatidylcholine at a reduced rate and accumulated increased amounts of methylated phospholipid intermediates. It was also found to be auxotrophic for inositol and allelic to an existing series of ino4 mutants. The ino2 and ino4 mutants, originally isolated on the basis of an inositol requirement, are unable to derepress the cytoplasmic enzyme inositol-1-phosphate synthase (myo-inositol-1-phosphate synthase; EC 5.5.1.4). The INO4 and INO2 genes were, thus, previously identified as regulatory genes whose wild-type product is required for expression of the INO1 gene product inositol-1-phosphate synthase (T. Donahue and S. Henry, J. Biol. Chem. 256:7077-7085, 1981). In addition to the identification of a new ino4-allele, further characterization of the existing series of ino4 and ino2 mutants, reported here, demonstrated that they all have a reduced capacity to convert phosphatidylethanolamine to phosphatidylcholine. The pleiotropic phenotype of the ino2 and ino4 mutants described in this paper suggests that the INO2 and INO4 loci are involved in the regulation of phospholipid methylation in the membrane as well as inositol biosynthesis in the cytoplasm. Images PMID:6392853

  6. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus.

    PubMed

    Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L; Kreiner, Eskil; Chesi, Alessandra; Zemel, Babette S; Bønnelykke, Klaus; Boer, Cindy G; Ahluwalia, Tarunveer S; Bisgaard, Hans; Evangelou, Evangelos; Heppe, Denise H M; Bonewald, Lynda F; Gorski, Jeffrey P; Ghanbari, Mohsen; Demissie, Serkalem; Duque, Gustavo; Maurano, Matthew T; Kiel, Douglas P; Hsu, Yi-Hsiang; C J van der Eerden, Bram; Ackert-Bicknell, Cheryl; Reppe, Sjur; Gautvik, Kaare M; Raastad, Truls; Karasik, David; van de Peppel, Jeroen; Jaddoe, Vincent W V; Uitterlinden, André G; Tobias, Jonathan H; Grant, Struan F A; Bagos, Pantelis G; Evans, David M; Rivadeneira, Fernando

    2017-07-25

    Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

  7. A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers

    PubMed Central

    Benton, Miles C.; Lea, Rodney A.; Macartney-Coxson, Donia; Hanna, Michelle; Eccles, David A.; Carless, Melanie A.; Chambers, Geoffrey K.; Bellis, Claire; Goring, Harald H.; Curran, Joanne E.; Harper, Jacquie L.; Gibson, Gregory; Blangero, John; Griffiths, Lyn R.

    2015-01-01

    Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk. PMID:26474483

  8. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

    PubMed

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J; Li, Qiyuan; Delgado, Melissa K; Lee, Janet M; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Bandera, Elisa V; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Matthias W; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B M; Cook, Linda S; Cox, Angela; Cramer, Daniel W; Cross, Simon S; Cybulski, Cezary; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Engel, Christoph; Lee, Eunjung; Evans, D Gareth; Fasching, Peter A; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fridley, Brooke L; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A; Garber, Judy; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G; Glasspool, Rosalind; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goode, Ellen L; Goodman, Marc T; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K; Hogervorst, Frans B L; Hollestelle, Antoinette; Hopper, John L; Hulick, Peter J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y; Khan, Sofia; Kiemeney, Lambertus A; Kjaer, Susanne Kruger; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; de la Hoya, Miguel; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F A G; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Milne, Roger L; Montagna, Marco; Moysich, Kirsten B; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Poole, Elizabeth M; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schildkraut, Joellen M; Schmidt, Marjanka K; Schmutzler, Rita K; Sellers, Thomas A; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F; Sinilnikova, Olga M; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tung, Nadine; Tworoger, Shelley S; Vachon, Celine; van den Ouweland, Ans M W; van Doorn, Helena C; van Rensburg, Elizabeth J; Van't Veer, Laura J; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wildiers, Hans; Winqvist, Robert; Wu, Anna H; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N; French, Juliet D; Couch, Fergus J; Freedman, Matthew L; Easton, Douglas F; Dunning, Alison M; Pharoah, Paul D; Edwards, Stacey L; Chenevix-Trench, Georgia; Antoniou, Antonis C; Gayther, Simon A

    2016-09-07

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  9. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

    PubMed Central

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Bandera, Elisa V.; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Matthias W.; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S.; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B. M.; Collonge-Rame, Marie- Agnès; Damette, Alexandre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Berthet, Pascaline; Vaur, Dominique; Castera, Laurent; Ferrer, Sandra Fert; Bignon, Yves-Jean; Uhrhammer, Nancy; Coron, Fanny; Faivre, Laurence; Baurand, Amandine; Jacquot, Caroline; Bertolone, Geoffrey; Lizard, Sarab; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Adenis, Claude; Vénat-Bouvet, Laurence; Léone, Mélanie; Boutry-Kryza, Nadia; Calender, Alain; Giraud, Sophie; Verny-Pierre, Carole; Lasset, Christine; Bonadona, Valérie; Barjhoux, Laure; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Coupier, Isabelle; Pujol, Pascal; Sokolowska, Johanna; Bronner, Myriam; Delnatte, Capucine; Bézieau, Stéphane; Mari, Véronique; Gauthier-Villars, Marion; Buecher, Bruno; Rouleau, Etienne; Golmard, Lisa; Moncoutier, Virginie; Belotti, Muriel; de Pauw, Antoine; Elan, Camille; Fourme, Emmanuelle; Birot, Anne-Marie; Saule, Claire; Laurent, Maïté; Houdayer, Claude; Lesueur, Fabienne; Mebirouk, Noura; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Warcoin, Mathilde; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Muller, Danièle; Fricker, Jean-Pierre; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Mortemousque, Isabelle; Bressac-de-Paillerets, Brigitte; Caron, Olivier; Guillaud-Bataille, Marine; Cook, Linda S.; Cox, Angela; Cramer, Daniel W.; Cross, Simon S.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A.; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Gregory, Helen; Miedzybrodzka, Zosia; Morrison, Patrick J.; Donaldson, Alan; Rogers, Mark T.; Kennedy, M. John; Porteous, Mary E.; Brady, Angela; Barwell, Julian; Foo, Claire; Lalloo, Fiona; Side, Lucy E.; Eason, Jacqueline; Henderson, Alex; Walker, Lisa; Cook, Jackie; Snape, Katie; Murray, Alex; McCann, Emma; Engel, Christoph; Lee, Eunjung; Evans, D. Gareth; Fasching, Peter A.; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D.; Fridley, Brooke L.; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A.; Garber, Judy; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G.; Glasspool, Rosalind; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Goode, Ellen L.; Goodman, Marc T.; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V. O.; Harrington, Patricia A.; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Rookus, M. A.; van Leeuwen, F. E.; van der Kolk, L. E.; Schmidt, M. K.; Russell, N. S.; de Lange, J. L.; Wijnands, R.; Collée, J. M.; Hooning, M. J.; Seynaeve, C.; van Deurzen, C. H. M.; Obdeijn, I. M.; van Asperen, C. J.; Tollenaar, R. A. E. M.; van Cronenburg, T. C. T. E. F.; Kets, C. M.; Ausems, M. G. E. M.; van der Pol, C. C.; van Os, T. A. M.; Waisfisz, Q.; Meijers-Heijboer, H. E. J.; Gómez-Garcia, E. B.; Oosterwijk, J. C.; Mourits, M. J.; de Bock, G. H.; Vasen, H. F.; Siesling, S.; Verloop, J.; Overbeek, L. I. H.; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K.; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hopper, John L.; Hulick, Peter J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Fox, Stephen; Kirk, Judy; Lindeman, Geoff; Price, Melanie; Bowtell, David; deFazio, Anna; Webb, Penny; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y.; Khan, Sofia; Kiemeney, Lambertus A.; Kjaer, Susanne Kruger; Knight, Julia A.; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; de la Hoya, Miguel; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A.; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T.; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F. A. G.; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Milne, Roger L.; Montagna, Marco; Moysich, Kirsten B.; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L.; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L.; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Poole, Elizabeth M.; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A.; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schildkraut, Joellen M.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Sellers, Thomas A.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F.; Sinilnikova, Olga M.; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C.; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R.; Teo, Soo H.; Terry, Kathryn L.; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-chen; Tung, Nadine; Tworoger, Shelley S.; Vachon, Celine; van den Ouweland, Ans M. W.; van Doorn, Helena C.; van Rensburg, Elizabeth J.; Van't Veer, Laura J.; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wildiers, Hans; Winqvist, Robert; Wu, Anna H.; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N.; French, Juliet D.; Couch, Fergus J.; Freedman, Matthew L.; Easton, Douglas F.; Dunning, Alison M.; Pharoah, Paul D.; Edwards, Stacey L.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Gayther, Simon A.

    2016-01-01

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. PMID:27601076

  10. High-resolution analysis of cis-acting regulatory networks at the α-globin locus.

    PubMed

    Hughes, Jim R; Lower, Karen M; Dunham, Ian; Taylor, Stephen; De Gobbi, Marco; Sloane-Stanley, Jacqueline A; McGowan, Simon; Ragoussis, Jiannis; Vernimmen, Douglas; Gibbons, Richard J; Higgs, Douglas R

    2013-01-01

    We have combined the circular chromosome conformation capture protocol with high-throughput, genome-wide sequence analysis to characterize the cis-acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10-1000 kb), the 4C approach provides a comprehensive, high-resolution analysis of a specific locus with the aim of defining, in detail, the cis-regulatory elements controlling a single gene or gene cluster. Using the human α-globin locus as a model, we detected all known local and long-range interactions with this gene cluster. In addition, we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the α-globin cluster.

  11. The sae locus of Staphylococcus aureus encodes a two-component regulatory system.

    PubMed

    Giraudo, A T; Calzolari, A; Cataldi, A A; Bogni, C; Nagel, R

    1999-08-01

    Sae is a regulatory locus that activates the production of several exoproteins in Staphylococcus aureus. A 3.4-kb fragment of a S. aureus genomic library, screened with a probe adjacent to the transposon insertion of a sae::Tn551 mutant, was cloned into a bifunctional vector. This fragment was shown to carry the sae locus by restoration of exoprotein production in sae mutants. The sae locus was mapped to the SmaI-D fragment of the staphylococcal chromosome by pulse-field electrophoresis. Sequence analysis of the cloned fragment revealed the presence of two genes, designated saeR and saeS, encoding a response regulator and a histidine protein kinase, respectively, with high homology to other bacterial two-component regulatory systems.

  12. Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin

    PubMed Central

    Makitrynskyy, Roman; Ostash, Bohdan; Tsypik, Olga; Rebets, Yuriy; Doud, Emma; Meredith, Timothy; Luzhetskyy, Andriy; Bechthold, Andreas; Walker, Suzanne; Fedorenko, Victor

    2013-01-01

    Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production—bldA, adpA and absB—exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNALeuUAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs—that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining. PMID:24153004

  13. Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context.

    PubMed

    Rask-Andersen, Mathias; Almén, Markus Sällman; Schiöth, Helgi B

    2015-11-01

    Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin-chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster.

  14. cis-Regulatory remodeling of the SCL locus during vertebrate evolution.

    PubMed

    Göttgens, Berthold; Ferreira, Rita; Sanchez, Maria-José; Ishibashi, Shoko; Li, Juan; Spensberger, Dominik; Lefevre, Pascal; Ottersbach, Katrin; Chapman, Michael; Kinston, Sarah; Knezevic, Kathy; Hoogenkamp, Maarten; Follows, George A; Bonifer, Constanze; Amaya, Enrique; Green, Anthony R

    2010-12-01

    Development progresses through a sequence of cellular identities which are determined by the activities of networks of transcription factor genes. Alterations in cis-regulatory elements of these genes play a major role in evolutionary change, but little is known about the mechanisms responsible for maintaining conserved patterns of gene expression. We have studied the evolution of cis-regulatory mechanisms controlling the SCL gene, which encodes a key transcriptional regulator of blood, vasculature, and brain development and exhibits conserved function and pattern of expression throughout vertebrate evolution. SCL cis-regulatory elements are conserved between frog and chicken but accrued alterations at an accelerated rate between 310 and 200 million years ago, with subsequent fixation of a new cis-regulatory pattern at the beginning of the mammalian radiation. As a consequence, orthologous elements shared by mammals and lower vertebrates exhibit functional differences and binding site turnover between widely separated cis-regulatory modules. However, the net effect of these alterations is constancy of overall regulatory inputs and of expression pattern. Our data demonstrate remarkable cis-regulatory remodelling across the SCL locus and indicate that stable patterns of expression can mask extensive regulatory change. These insights illuminate our understanding of vertebrate evolution.

  15. Construction of an integrative regulatory element and variation map of the murine Tst locus.

    PubMed

    Beltram, Jasmina; Morton, Nicholas M; Kunej, Tanja; Horvat, Simon

    2016-06-11

    Given the abundance of new genomic projects and gene annotations, researchers trying to pinpoint causal genetic variants are faced with a challenging task of how to efficiently integrate all current genomic information. The objective of the study was to develop an approach to integrate various genomic annotations for a recently positionally-cloned Tst gene (Thiosulfate Sulfur Transferase, synonym Rhodanese) responsible for the Fob3b2 QTL effect on leanness and improved metabolic parameters. The second aim was to identify and prioritize Tst genetic variants that may be causal for the phenotypic effects. A bioinformatics approach was developed to integrate existing knowledge of regulatory elements of the Tst gene. The entire Tst locus along with flanking segments was sequenced between our unique polygenic mouse Fat and Lean strains that were generated by divergent selection on adiposity for over 60 generations. The bioinformatics-generated regulatory element map of the Tst locus was then combined with genetic variants between the Fat and Lean mice and with comparative analyses of polymorphisms across 17 mouse strains in order to prioritise likely causal polymorphisms. Two candidate regulatory variants were identified, one overlapping an evolutionary constrained Tst intronic element and the other residing in the seed region of a predicted 3'UTR miRNA binding site. This study developed a map of regulatory elements for the Tst locus in mice and identified candidate genetic variants with increased causal likelihood. This map provides a basis for experimental validation and functional analyses of this novel candidate leanness and antidiabetic gene. Our methodological approach is of general utility for analyzing regulation of loci that have limited annotations and experimental evidence and for identifying candidate causal regulatory genetic variants in post-GWAS or post-QTL- cloning studies.

  16. Hybrid Incompatibility Despite Pleiotropic Constraint in a Sequence-Based Bioenergetic Model of Transcription Factor Binding

    PubMed Central

    Tulchinsky, Alexander Y.; Johnson, Norman A.; Porter, Adam H.

    2014-01-01

    Hybrid incompatibility can result from gene misregulation produced by divergence in trans-acting regulatory factors and their cis-regulatory targets. However, change in trans-acting factors may be constrained by pleiotropy, which would in turn limit the evolution of incompatibility. We employed a mechanistically explicit bioenergetic model of gene expression wherein parameter combinations (number of transcription factor molecules, energetic properties of binding to the regulatory site, and genomic background size) determine the shape of the genotype–phenotype (G-P) map, and interacting allelic variants of mutable cis and trans sites determine the phenotype along that map. Misregulation occurs when the phenotype differs from its optimal value. We simulated a pleiotropic regulatory pathway involving a positively selected and a conserved trait regulated by a shared transcription factor (TF), with two populations evolving in parallel. Pleiotropic constraints shifted evolution in the positively selected trait to its cis-regulatory locus. We nevertheless found that the TF genotypes often evolved, accompanied by compensatory evolution in the conserved trait, and both traits contributed to hybrid misregulation. Compensatory evolution resulted in “developmental system drift,” whereby the regulatory basis of the conserved phenotype changed although the phenotype itself did not. Pleiotropic constraints became stronger and in some cases prohibitive when the bioenergetic properties of the molecular interaction produced a G-P map that was too steep. Likewise, compensatory evolution slowed and hybrid misregulation was not evident when the G-P map was too shallow. A broad pleiotropic “sweet spot” nevertheless existed where evolutionary constraints were moderate to weak, permitting substantial hybrid misregulation in both traits. None of these pleiotropic constraints manifested when the TF contained nonrecombining domains independently regulating the respective traits

  17. Hybrid incompatibility despite pleiotropic constraint in a sequence-based bioenergetic model of transcription factor binding.

    PubMed

    Tulchinsky, Alexander Y; Johnson, Norman A; Porter, Adam H

    2014-12-01

    Hybrid incompatibility can result from gene misregulation produced by divergence in trans-acting regulatory factors and their cis-regulatory targets. However, change in trans-acting factors may be constrained by pleiotropy, which would in turn limit the evolution of incompatibility. We employed a mechanistically explicit bioenergetic model of gene expression wherein parameter combinations (number of transcription factor molecules, energetic properties of binding to the regulatory site, and genomic background size) determine the shape of the genotype-phenotype (G-P) map, and interacting allelic variants of mutable cis and trans sites determine the phenotype along that map. Misregulation occurs when the phenotype differs from its optimal value. We simulated a pleiotropic regulatory pathway involving a positively selected and a conserved trait regulated by a shared transcription factor (TF), with two populations evolving in parallel. Pleiotropic constraints shifted evolution in the positively selected trait to its cis-regulatory locus. We nevertheless found that the TF genotypes often evolved, accompanied by compensatory evolution in the conserved trait, and both traits contributed to hybrid misregulation. Compensatory evolution resulted in "developmental system drift," whereby the regulatory basis of the conserved phenotype changed although the phenotype itself did not. Pleiotropic constraints became stronger and in some cases prohibitive when the bioenergetic properties of the molecular interaction produced a G-P map that was too steep. Likewise, compensatory evolution slowed and hybrid misregulation was not evident when the G-P map was too shallow. A broad pleiotropic "sweet spot" nevertheless existed where evolutionary constraints were moderate to weak, permitting substantial hybrid misregulation in both traits. None of these pleiotropic constraints manifested when the TF contained nonrecombining domains independently regulating the respective traits. Copyright

  18. Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche.

    PubMed

    Tan, Li-Jun; Wang, Zhuo-Er; Wu, Ke-Hao; Chen, Xiang-Ding; Zhu, Hu; Lu, Shan; Tian, Qing; Liu, Xiao-Gang; Papasian, Christopher J; Deng, Hong-Wen

    2015-11-01

    Age at menarche (AAM) is determined by the overall duration of endocrine-tissue sex hormone exposure levels. Osteoporosis, the most common metabolic bone disease, is characterized primarily by reduced bone mineral density (BMD) and an increased risk of low trauma fractures. Bone was an endocrine organ regulating the synthesis and secretion of sex steroid hormones. The mutual dependence between bone and gonads underscore the importance of genetic approaches to identify novel pleiotropic genetic factors coregulating BMD and AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to explore novel ethnic common loci and/or genes that may influence both AAM and BMD. We analyzed genotyping data available for 826 unrelated Chinese subjects using genome-wide human genotyping arrays. After quality control, a total of 702 413 single-nucleotide polymorphisms (SNPs) were tested for association using a bivariate linear regression model. The interesting SNPs were replicated in three independent cohorts including 1728 unrelated Caucasians, 709 African-Americans, and 408 Hispanic-Americans. We found four SNPs (rs10817638, rs7851259, rs10982287, and rs4979427), located upstream of the ATP6V1G1 gene, were bivariately associated with hip BMD-AAM (P = 4.90 × 10(-7), P = 1.07 × 10(-6), P = 1.28 × 10(-5), and P = 5.42 × 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 × 10(-2), P = 3.18 × 10(-2), P = 2.57 × 10(-2), and P = 3.64 × 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 × 10(-2) and P = 9.42 × 10(-3), respectively) and Hispanic-Americans (P = 8.37 × 10(-3) and P = 1.52 × 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 × 10(-9) and P = 3.49 × 10(-9), respectively. Our study implicated ATP6V1G1 as a novel pleiotropic gene underlying variation

  19. Identification of the regulatory sequence of anaerobically expressed locus aeg-46.5.

    PubMed Central

    Choe, M; Reznikoff, W S

    1993-01-01

    A newly identified anaerobically expressed locus, aeg-46.5, which is located at min 46.5 on Escherichia coli linkage map, was cloned and analyzed. The phenotype of this gene was studied by using a lacZ operon fusion. aeg-46.5 is induced anaerobically in the presence of nitrate in wild-type and narL cells. It is repressed by the narL gene product, as it showed derepressed anaerobic expression in narL mutant cells. We postulate that aeg-46.5 is subject to multiple regulatory systems, activation as a result of anaerobiosis, narL-independent nitrate-dependent activation, and narL-mediated repression. The regulatory region of aeg-46.5 was identified. A 304-bp DNA sequence which includes the regulatory elements was obtained, and the 5' end of aeg-46.5 mRNA was identified. It was verified that the anaerobic regulation of aeg-46.5 expression is controlled on the transcriptional level. Computer analysis predicted possible control sites for the NarL and FNR proteins. The proposed NarL site was found in a perfect-symmetry element. The aeg-46.5 regulatory elements are adjacent to, but divergent from, those of the eco gene. Images PMID:8432709

  20. Molecular basis of the pleiotropic phenotype of mice carrying the hypervariable yellow (A{sup hvy}) mutation at the agouti locus

    SciTech Connect

    Argeson, A.C.; Nelson, K.K.; Siracusa, L.D.

    1996-02-01

    The murine agouti locus regulates a switch in pigment synthesis between eumelanin (black/brown pigment) and phaeomelanin (yellow/red pigment) by hair bulb melanocytes. We recently described a spontaneous mutation, hypervariable yellow (A{sup hvy}) and demonstrated that A{sup hvy} is responsible for the largest range of phenotypes yet identified at the agouti locus, producing mice that are obese with yellow coats to mice that are of normal weight with black coats. Here, we show that agouti expression is altered both temporally and spatially in A{sup hvy} mutants. Agouti expression levels are positively correlated with the degree of yellow pigmentation in individual A{sup hvy} mice, consistent with results from other dominant yellow agouti mutations. Sequencing of 5{prime} RACE and genomic PCR products revealed that A{sup hvy} resulted from the integration of an intracisternal A particle (IAP) in an antisense orientation within the 5{prime} untranslated agouti exon 1C. This retrovirus-like element is responsible for deregulating agouti expression in A{sup hvy} mice; agouti expression is correlated with the methylation state of CpG residues in the IAP long terminal repeat as well as in host genomic DNA. In addition, the data suggest that the variable phenotype of A{sup hvy} offspring is influenced in part by the phenotype of their A{sup hvy} female parent. 42 refs., 7 figs., 1 tab.

  1. The pleiotropic nature of symbiotic regulatory mutants: Bradyrhizobium japonicum nifA gene is involved in control of nif gene expression and formation of determinate symbiosis

    PubMed Central

    Fischer, Hans-Martin; Alvarez-Morales, Ariel; Hennecke, Hauke

    1986-01-01

    In the slow-growing soybean symbiont, Bradyrhizobium japonicum (strain 110), a nifA-like regulatory gene was located immediately upstream of the previously mapped fixA gene. By interspecies hybridization and partial DNA sequencing the gene was found to be homologous to nifA from Klebsiella pneumoniae and Rhizobium meliloti, and to a lesser extent, also to ntrC from K. pneumoniae. The B. japonicum nifA gene product was shown to activate B. japonicum and K. pneumoniae nif promoters (using nif::lacZ translational fusions) both in Escherichia coli and B. japonicum backgrounds. In the heterologous E. coli system activation was shown to be dependent on the ntrA gene product. Site-directed insertion and deletion/replacement mutagenesis revealed that nifA is probably the promoter-distal cistron within an operon. NifA- mutants were Fix- and pleiotropic: (i) they were defective in the synthesis of several proteins including the nifH gene product (nitrogenase Fe protein); the same proteins had been known to be repressed under aerobic growth of B. japonicum but derepressed at low O2 tension; (ii) the mutants had an altered nodulation phenotype inducing numerous, small, widely distributed soybean nodules in which the bacteroids were subject to severe degradation. These results show that nifA not only controls nitrogenase genes but also one or more genes involved in the establishment of a determinate, nitrogen-fixing root nodule symbiosis. ImagesFig. 4.Fig. 5. PMID:15966104

  2. Validation and characterization of Ghd7.1, a major quantitative trait locus with pleiotropic effects on spikelets per panicle, plant height, and heading date in rice (Oryza sativa L.).

    PubMed

    Liu, Touming; Liu, Haiyang; Zhang, Huang; Xing, Yongzhong

    2013-10-01

    A quantitative trait locus (QTL) that affects heading date (HD) and the number of spikelets per panicle (SPP) was previously identified in a small region on chromosome 7 in rice (Oryza sativa L.). In order to further characterize the QTL region, near isogenic lines (NILs) were quickly obtained by self-crossing recombinant inbred line 189, which is heterozygous in the vicinity of the target region. The pleiotropic effects of QTL Ghd7.1 on plant height (PH), SPP, and HD, were validated using an NIL-F2 population. Ghd7.1 explained 50.2%, 45.3%, and 76.9% of phenotypic variation in PH, SPP, and HD, respectively. Ghd7.1 was precisely mapped to a 357-kb region on the basis of analysis of the progeny of the NIL-F2 population. Day-length treatment confirmed that Ghd7.1 is sensitive to photoperiod, with long days delaying heading up to 12.5 d. Identification of panicle initiation and development for the pair of NILs showed that Ghd7.1 elongated the photoperiod-sensitive phase more than 10 d, but did not change the basic vegetative phase and the reproductive growth phase. These findings indicated that Ghd7.1 regulates SPP by controlling the rate of panicle differentiation rather than the duration of panicle development. © 2013 Institute of Botany, Chinese Academy of Sciences.

  3. Studies on the expression of regulatory locus sae in Staphylococcus aureus.

    PubMed

    Giraudo, Ana T; Mansilla, Cecilia; Chan, Ana; Raspanti, Claudia; Nagel, Rosa

    2003-04-01

    Global regulatory locus sae consists of a two-component signal transduction system coded by saeR and saeS genes that upregulates the transcription of several exoproteins. Northern analysis carried out in this study reveals the synthesis at late and post-exponential phases of a cotranscript of saeR and saeS structural genes of about 2.4 kb. This transcript is diminished in the isogenic agr:: tetM mutant. Likewise, transcriptional fusion experiments show that sae expression is downregulated in the agr null mutant. Complementation analyses with plasmids carrying fragments of about 1.2 or 0.2 kbp upstream of saeR-saeS genes, which restore fully or only partially, respectively, the wild-type phenotype to the sae mutant, are in agreement with two initiation start points of transcription revealed by primer extension experiments. This work, as well as previous studies, reveals a complex hierarchical regulatory network involving several loci that control the expression of virulence determinants in S. aureus.

  4. The RNA binding protein CsrA is a pleiotropic regulator of the locus of enterocyte effacement pathogenicity island of enteropathogenic Escherichia coli.

    PubMed

    Bhatt, Shantanu; Edwards, Adrianne Nehrling; Nguyen, Hang Thi Thu; Merlin, Didier; Romeo, Tony; Kalman, Daniel

    2009-09-01

    The attaching and effacing (A/E) pathogen enteropathogenic Escherichia coli (EPEC) forms characteristic actin-filled membranous protrusions upon infection of host cells termed pedestals. Here we examine the role of the RNA binding protein CsrA in the expression of virulence genes and proteins that are necessary for pedestal formation. The csrA mutant was defective in forming actin pedestals on epithelial cells and in disrupting transepithelial resistance across polarized epithelial cells. Consistent with reduced pedestal formation, secretion of the translocators EspA, EspB, and EspD and the effector Tir was substantially reduced in the csrA mutant. Purified CsrA specifically bound to the sepL espADB mRNA leader, and the corresponding transcript levels were reduced in the csrA mutant. In contrast, Tir synthesis was unaffected in the csrA mutant. Reduced secretion of Tir appeared to be in part due to decreased synthesis of EscD, an inner membrane architectural protein of the type III secretion system (TTSS) and EscF, a protein that forms the protruding needle complex of the TTSS. These effects were not mediated through the locus of enterocyte effacement (LEE) transcriptional regulator GrlA or Ler. In contrast to the csrA mutant, multicopy expression of csrA repressed transcription from LEE1, grlRA, LEE2, LEE5, escD, and LEE4, an effect mediated by GrlA and Ler. Consistent with its role in other organisms, CsrA also regulated flagellar motility and glycogen levels. Our findings suggest that CsrA governs virulence factor expression in an A/E pathogen by regulating mRNAs encoding translocators, effectors, or transcription factors.

  5. Identification and Potential Regulatory Properties of Evolutionary Conserved Regions (ECRs) at the Schizophrenia-Associated MIR137 Locus.

    PubMed

    Gianfrancesco, Olympia; Griffiths, Daniel; Myers, Paul; Collier, David A; Bubb, Vivien J; Quinn, John P

    2016-10-01

    Genome-wide association studies (GWAS) have identified a region at chromosome 1p21.3, containing the microRNA MIR137, to be among the most significant associations for schizophrenia. However, the mechanism by which genetic variation at this locus increases risk of schizophrenia is unknown. Identifying key regulatory regions around MIR137 is crucial to understanding the potential role of this gene in the aetiology of psychiatric disorders. Through alignment of vertebrate genomes, we identified seven non-coding regions at the MIR137 locus with conservation comparable to exons (>70 %). Bioinformatic analysis using the Psychiatric Genomics Consortium GWAS dataset for schizophrenia showed five of the ECRs to have genome-wide significant SNPs in or adjacent to their sequence. Analysis of available datasets on chromatin marks and histone modification data showed that three of the ECRs were predicted to be functional in the human brain, and three in development. In vitro analysis of ECR activity using reporter gene assays showed that all seven of the selected ECRs displayed transcriptional regulatory activity in the SH-SY5Y neuroblastoma cell line. This data suggests a regulatory role in the developing and adult brain for these highly conserved regions at the MIR137 schizophrenia-associated locus and further that these domains could act individually or synergistically to regulate levels of MIR137 expression.

  6. Disruption of a novel regulatory locus results in decreased Bdnf expression, obesity, and type 2 diabetes in mice.

    PubMed

    Sha, Haibo; Xu, Jingyue; Tang, Jing; Ding, Jun; Gong, Jianfeng; Ge, Xiaomei; Kong, Dong; Gao, Xiang

    2007-10-22

    Mutants of brain-derived neurotrophic factor (BDNF) are associated with obesity. However, the regulatory mechanism of BDNF expression is still unclear. We developed a novel mutant mouse line, transgenic insertional mutants with obesity, named Timo, in which a potential regulatory locus of Bdnf was disrupted by transgene insertion. The insertion site was identified and lies 857 kb upstream of the Bdnf gene. The disrupted genomic locus is conserved across the mouse, rat, dog, and human genome and contains several highly conserved elements that are able to upregulate reporter gene expression in vitro. Along with downregulation of BDNF to approximately 30% of wild-type animals, Timo/Timo mice exhibited increased body weight and fat content with hepatic steatosis and elevated serum levels of leptin, cholesterol, and LDL cholesterol. These mutant mice also showed obesity-independent insulin resistance, hyperinsulinemia, impaired glucose tolerance, age-dependent hyperglycemia, and shortened life span. Molecular and phenotype analysis of Timo/Timo mice indicated the existence of a genome locus, lying 857 kb upstream of the Bdnf gene, that regulates BDNF expression, body weight, and glucose homeostasis.

  7. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.

    PubMed

    Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P; Vadlamudi, Swarooparani; Gonzalez, Arlene J; Buchkovich, Martin L; Huyghe, Jeroen R; Fuchsberger, Christian; Jackson, Anne U; Wu, Ying; Civelek, Mete; Lusis, Aldons J; Gaulton, Kyle J; Sethupathy, Praveen; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L

    2015-12-03

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus.

  8. Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus

    PubMed Central

    Yang, Rui; Kerschner, Jenny L.; Gosalia, Nehal; Neems, Daniel; Gorsic, Lidija K.; Safi, Alexias; Crawford, Gregory E.; Kosak, Steven T.; Leir, Shih-Hsing; Harris, Ann

    2016-01-01

    Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene provides a paradigm for investigating these mechanisms. CFTR occupies a TAD bordered by CTCF/cohesin binding sites within which are cell-type-selective cis-regulatory elements for the locus. We showed previously that intronic and extragenic enhancers, when occupied by specific transcription factors, are recruited to the CFTR promoter by a looping mechanism to drive gene expression. Here we use a combination of CRISPR/Cas9 editing of cis-regulatory elements and siRNA-mediated depletion of architectural proteins to determine the relative contribution of structural elements and enhancers to the higher order structure and expression of the CFTR locus. We found the boundaries of the CFTR TAD are conserved among diverse cell types and are dependent on CTCF and cohesin complex. Removal of an upstream CTCF-binding insulator alters the interaction profile, but has little effect on CFTR expression. Within the TAD, intronic enhancers recruit cell-type selective transcription factors and deletion of a pivotal enhancer element dramatically decreases CFTR expression, but has minor effect on its 3D structure. PMID:26673704

  9. New cis-regulatory elements in the Rht-D1b locus region of wheat

    USDA-ARS?s Scientific Manuscript database

    Fifteen gene-containing BACs with accumulated length of 1.82-Mb from the Rht-D1b locus region weresequenced and compared in detail with the orthologous regions of rice, sorghum, and maize. Our results show that Rht-D1b represents a conserved genomic region as implied by high gene sequence identity...

  10. Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids.

    PubMed

    Lu, Yuan; Boswell, Mikki; Boswell, William; Kneitz, Susanne; Hausmann, Michael; Klotz, Barbara; Regneri, Janine; Savage, Markita; Amores, Angel; Postlethwait, John; Warren, Wesley; Schartl, Manfred; Walter, Ronald

    2017-08-01

    Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA-Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1 ) hybrids and 13 fifth generation (BC5 ) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor-bearing BC1 hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty-one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development. © 2017 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals Inc.

  11. The zebrafish IgH locus contains multiple transcriptional regulatory regions

    PubMed Central

    Danilova, N.; Saunders, H. L.; Ellestad, K. K.; Magor, B. G.

    2010-01-01

    Many fish have, in addition to IgM and IgD, a third isotype called IgZ or IgT. The ζ-chain locus is embedded among the Ig heavy chain V-, D- and J-elements in a manner reminiscent of the TcR δ/α locus. Isotype selection thus occurs during VDJ recombination, a process that is facilitated by intralocus transcription. Using in silico analyses and enhancer reporter vectors we identified 3 new regions within the zebrafish IgH locus through which transcription can be activated in catfish B-cell lines. Two of these, termed Eζi (Jζ to Cζ1 intronic) and Eζ3′ regions flank the ζ-chain constant domain exons. A third region, Eδ3′, resides downstream of the δ-chain exons. All regions contain predicted binding sites for transcription factors that contribute to B-cell specific transcription in fish and mammals. Each region also has proximal matrix attachment regions, which may further contribute to transcriptional activation and chromatin remodeling. We discuss possible roles for these regions during VDJ recombination. PMID:21055416

  12. A putative regulatory genetic locus modulates virulence in the pathogen Leptospira interrogans.

    PubMed

    Eshghi, Azad; Becam, Jérôme; Lambert, Ambroise; Sismeiro, Odile; Dillies, Marie-Agnès; Jagla, Bernd; Wunder, Elsio A; Ko, Albert I; Coppee, Jean-Yves; Goarant, Cyrille; Picardeau, Mathieu

    2014-06-01

    Limited research has been conducted on the role of transcriptional regulators in relation to virulence in Leptospira interrogans, the etiological agent of leptospirosis. Here, we identify an L. interrogans locus that encodes a sensor protein, an anti-sigma factor antagonist, and two genes encoding proteins of unknown function. Transposon insertion into the gene encoding the sensor protein led to dampened transcription of the other 3 genes in this locus. This lb139 insertion mutant (the lb139(-) mutant) displayed attenuated virulence in the hamster model of infection and reduced motility in vitro. Whole-transcriptome analyses using RNA sequencing revealed the downregulation of 115 genes and the upregulation of 28 genes, with an overrepresentation of gene products functioning in motility and signal transduction and numerous gene products with unknown functions, predicted to be localized to the extracellular space. Another significant finding encompassed suppressed expression of the majority of the genes previously demonstrated to be upregulated at physiological osmolarity, including the sphingomyelinase C precursor Sph2 and LigB. We provide insight into a possible requirement for transcriptional regulation as it relates to leptospiral virulence and suggest various biological processes that are affected due to the loss of native expression of this genetic locus.

  13. Pigmentation and behavior: potential association through pleiotropic genes in Drosophila.

    PubMed

    Takahashi, Aya

    2013-01-01

    The molecular basis of pigmentation variation within and among Drosophila species is largely attributed to genes in melanin biosynthesis pathway, which involves dopamine metabolism. Most of the genetic changes underlying pigmentation variations reported to date are changes at the expression levels of the structural genes in the pathway. Within D. melanogaster, changes in cis-regulatory regions of a gene, ebony, are responsible for the naturally occurring variation of the body pigmentation intensity. This gene is also known to be expressed in glia, and many visual and behavioral abnormalities of its mutants have been reported. This implies that the gene has pleiotropic functions in the nervous systems. In this review, current knowledge on pigmentation variation and melanin biosynthesis pathway are summarized, with some focus on pleiotropic features of ebony and other genes in the pathway. A potential association between pigmentation and behavior through such pleiotropic genes is discussed in light of cis-regulatory structure and pleiotropic mutations.

  14. Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome.

    PubMed

    Du, Meijun; Yuan, Tiezheng; Schilter, Kala F; Dittmar, Rachel L; Mackinnon, Alexander; Huang, Xiaoyi; Tschannen, Michael; Worthey, Elizabeth; Jacob, Howard; Xia, Shu; Gao, Jianzhong; Tillmans, Lori; Lu, Yan; Liu, Pengyuan; Thibodeau, Stephen N; Wang, Liang

    2015-01-01

    Chromosome 8q24 locus contains regulatory variants that modulate genetic risk to various cancers including prostate cancer (PC). However, the biological mechanism underlying this regulation is not well understood. Here, we developed a chromosome conformation capture (3C)-based multi-target sequencing technology and systematically examined three PC risk regions at the 8q24 locus and their potential regulatory targets across human genome in six cell lines. We observed frequent physical contacts of this risk locus with multiple genomic regions, in particular, inter-chromosomal interaction with CD96 at 3q13 and intra-chromosomal interaction with MYC at 8q24. We identified at least five interaction hot spots within the predicted functional regulatory elements at the 8q24 risk locus. We also found intra-chromosomal interaction genes PVT1, FAM84B and GSDMC and inter-chromosomal interaction gene CXorf36 in most of the six cell lines. Other gene regions appeared to be cell line-specific, such as RRP12 in LNCaP, USP14 in DU-145 and SMIN3 in lymphoblastoid cell line. We further found that the 8q24 functional domains more likely interacted with genomic regions containing genes enriched in critical pathways such as Wnt signaling and promoter motifs such as E2F1 and TCF3. This result suggests that the risk locus may function as a regulatory hub by physical interactions with multiple genes important for prostate carcinogenesis. Further understanding genetic effect and biological mechanism of these chromatin interactions will shed light on the newly discovered regulatory role of the risk locus in PC etiology and progression.

  15. PLEIOTROPIC EFFECTS OF STATINS

    PubMed Central

    Liao, James K.; Laufs, Ulrich

    2009-01-01

    Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins. PMID:15822172

  16. A Positive Regulatory Loop Controls Expression of the Locus of Enterocyte Effacement-Encoded Regulators Ler and GrlA

    PubMed Central

    Barba, Jeannette; Bustamante, Víctor H.; Flores-Valdez, Mario A.; Deng, Wanyin; Finlay, B. Brett; Puente, José L.

    2005-01-01

    The formation of attaching and effacing (A/E) lesions on intestinal epithelial cells is an essential step in the pathogenesis of human enteropathogenic and enterohemorrhagic Escherichia coli and of the mouse pathogen Citrobacter rodentium. The genes required for the development of the A/E phenotype are located within a pathogenicity island known as the locus of enterocyte effacement (LEE). The LEE-encoded transcriptional regulators Ler, an H-NS-like protein, and GrlA, a member of a novel family of transcriptional activators, positively control the expression of the genes located in the LEE and their corresponding virulence. In this study, we used C. rodentium as a model to study the mechanisms controlling the expression of Ler and GrlA. By deletion analysis of the ler and grlRA regulatory regions and complementation experiments, negative and positive cis-acting regulatory motifs were identified that are essential for the regulation of both genes. This analysis confirmed that GrlA is required for the activation of ler, but it also showed that Ler is required for the expression of grlRA, revealing a novel regulatory loop controlling the optimal expression of virulence genes in A/E pathogens. Furthermore, our results indicate that Ler and GrlA induce the expression of each other by, at least in part, counteracting the repression mediated by H-NS. However, whereas GrlA is still required for the optimal expression of ler even in the absence of H-NS, Ler is not needed for the expression of grlRA in the absence of H-NS. This type of transcriptional positive regulatory loop represents a novel mechanism in pathogenic bacteria that is likely required to maintain an appropriate spatiotemporal transcriptional response during infection. PMID:16291665

  17. Maternal Depression, Locus of Control, and Emotion Regulatory Strategy as Predictors of Preschoolers' Internalizing Problems

    ERIC Educational Resources Information Center

    Coyne, Lisa W.; Thompson, Alysha D.

    2011-01-01

    Childhood internalizing problems may occur as early as preschool, tend to be stable over time, and undermine social and academic functioning. Parent emotion regulatory behaviors may contribute to child internalizing problems and may be especially important during the preschool years when parents model emotion coping and regulation for their…

  18. Maternal Depression, Locus of Control, and Emotion Regulatory Strategy as Predictors of Preschoolers' Internalizing Problems

    ERIC Educational Resources Information Center

    Coyne, Lisa W.; Thompson, Alysha D.

    2011-01-01

    Childhood internalizing problems may occur as early as preschool, tend to be stable over time, and undermine social and academic functioning. Parent emotion regulatory behaviors may contribute to child internalizing problems and may be especially important during the preschool years when parents model emotion coping and regulation for their…

  19. A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury.

    PubMed

    Guenther, Catherine A; Wang, Zhen; Li, Emma; Tran, Misha C; Logan, Catriona Y; Nusse, Roel; Pantalena-Filho, Luiz; Yang, George P; Kingsley, David M

    2015-08-01

    Bone morphogenetic proteins (BMPs) are key signaling molecules required for normal development of bones and other tissues. Previous studies have shown that null mutations in the mouse Bmp5 gene alter the size, shape and number of multiple bone and cartilage structures during development. Bmp5 mutations also delay healing of rib fractures in adult mutants, suggesting that the same signals used to pattern embryonic bone and cartilage are also reused during skeletal regeneration and repair. Despite intense interest in BMPs as agents for stimulating bone formation in clinical applications, little is known about the regulatory elements that control developmental or injury-induced BMP expression. To compare the DNA sequences that activate gene expression during embryonic bone formation and following acute injuries in adult animals, we assayed regions surrounding the Bmp5 gene for their ability to stimulate lacZ reporter gene expression in transgenic mice. Multiple genomic fragments, distributed across the Bmp5 locus, collectively coordinate expression in discrete anatomic domains during normal development, including in embryonic ribs. In contrast, a distinct regulatory region activated expression following rib fracture in adult animals. The same injury control region triggered gene expression in mesenchymal cells following tibia fracture, in migrating keratinocytes following dorsal skin wounding, and in regenerating epithelial cells following lung injury. The Bmp5 gene thus contains an "injury response" control region that is distinct from embryonic enhancers, and that is activated by multiple types of injury in adult animals.

  20. A pleiotropic model of phenotypic evolution.

    PubMed

    Tanaka, Y

    1998-01-01

    A pleiotropic model is presented for deriving the equilibrium genetic variance by mutation and stabilizing selection and the long-term genetic responses to directional selection in the case where mutations have pleiotropic effects on fitness itself (direct deleterious effect) and on a quantitative trait (phenotypic effect). The equilibrium genetic variance is derived as a general form of the rare-alleles models, i.e., [formula: see text], where n is the number of loci, mu is the per-locus mutation rate, alpha 2 is the variance of new mutations, V(s) is the measure of stabilizing selection, and s(u) is the selection coefficient on mutations by direct deleterious effect. The genetic responses to directional selection is calculated based on the assumption that the genetic variance is kept at an equilibrium by mutation and stabilizing selection but without directional selection, and the directional selection starts to operate on the target trait. The evolutionary rate at the t-th generation after the introduction of the directional selection is [formula: see text], where i is the directional selection intensity, and s(T) is the total selection coefficient on mutations, i.e., [formula: see text]. The selection limit is [formula: see text], where V(m) is the mutational variance (2n mu alpha 2). The pleiotropic effects of genes reduce both the evolutionary rate and the selection limit.

  1. Autoregulatory feedback controls sequential action of cis-regulatory modules at the brinker locus.

    PubMed

    Dunipace, Leslie; Saunders, Abbie; Ashe, Hilary L; Stathopoulos, Angelike

    2013-09-16

    cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, here we investigate the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Autoregulatory Feedback Controls Sequential Action of cis-Regulatory Modules at the brinker Locus

    PubMed Central

    Dunipace, Leslie; Saunders, Abbie; Ashe, Hilary L.; Stathopoulos, Angelike

    2013-01-01

    Summary cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, here we investigate the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development. PMID:24044892

  3. A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell

    PubMed Central

    Kulzer, Jennifer R.; Stitzel, Michael L.; Morken, Mario A.; Huyghe, Jeroen R.; Fuchsberger, Christian; Kuusisto, Johanna; Laakso, Markku; Boehnke, Michael; Collins, Francis S.; Mohlke, Karen L.

    2014-01-01

    Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7.4 × 10−50). Measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAP1 promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele. Collectively, these data suggest that the T2D-risk allele of rs11603334 could abrogate binding of a complex containing PAX6 and PAX4 and thus lead to increased promoter activity and ARAP1 expression in human pancreatic islets. This work suggests that increased ARAP1 expression might contribute to T2D susceptibility at this GWAS locus. PMID:24439111

  4. Regulatory elements necessary for termination of transcription within the immunoglobulin heavy chain gene locus

    SciTech Connect

    Moore, B.B.

    1992-01-01

    Previous experimentation demonstrated that regulation of the IgM only phenotype in both pre-B and immature B cells was primarily at the transcriptional level. Expression of IgD mRNA involves transcription of the entire 29 kilobase rearranged [mu]-[delta] locus. Mature B cells transcribe the [beta] exons at approximately half the level that they transcribe the [delta] gene. Early B cells however, transcribe the [mu] gene with approximately 90% more efficiency than they do the [delta] gene. Specifically, early B cells show a transcription termination event occurring within a 1 kilobase region of the [mu]-[delta] intron. This dissertation analyzes the sequence elements necessary to encode the transcription termination event within the [mu]-[delta] intron. This work shows that the termination motif consists of specific sequences within the [mu]m poly(A) site as well as a region of the [mu]-[delta] intron contained within a 1200 base pair fragment. The 1200 base pair fragment extends from the Pst I site within the intron and ends just prior to the C[delta]1 exon. This fragment contains a 162 base pair unique sequence inverted repeat (USIR). Furthermore, the [mu]m site is specifically required because the [mu]s site was unable to substitute, despite extensive usage. In addition, the USIR-containing intron functions in an orientation-dependent manner. Analysis of this termination motif in a variety of lymphoid and non-lymphoid cells suggests that this motif is an intrinsic polymerase II termination motif. This implies that transcription termination in early B cells is by a default model and that active regulation of this motif involves an anti-termination event in mature B cells.

  5. A complement of ten essential and pleiotropic arabidopsis COP/DET/FUS genes is necessary for repression of photomorphogenesis in darkness.

    PubMed Central

    Kwok, S F; Piekos, B; Misera, S; Deng, X W

    1996-01-01

    Two genetic screens, one for mutations resulting in photomorphogenic development in darkness and the other for mutants with fusca phenotype, have thus far identified six pleiotropic Arabidopsis COP/DET/FUS genes. Here, we characterized representative mutants that define four additional pleiotropic photomorphogenic loci and a null mutant allele of the previously defined DET1 locus. Dark-grown seedlings homozygous for these recessive mutations exhibit short hypocotyls and expanded cotyledons and are lethal before reaching reproductive development. Dark-grown mutant seedlings also display characteristic photomorphogenic cellular differentiation and elevated expression of light-inducible genes. In addition, analyses of plastids from dark-grown mutants reveal partial chloroplast differentiation and absence of etioplast development. Root vascular bundle cells of light-grown mutant seedlings develop chloroplasts, suggesting that these FUS gene products are important for suppression of chloroplast differentiation in light-grown roots. Double-mutant analyses indicate that these pleiotropic cop/det/fus mutations are epistatic to mutations in phytochromes, a blue-light photoreceptor, and a downstream regulatory component, HY5. Therefore, there is a complement of at least 10 essential and pleiotropic Arabidopsis genes that are necessary for repression of photomorphogenic development. PMID:8819865

  6. Identification of the Staphylococcus aureus vfrAB Operon, a Novel Virulence Factor Regulatory Locus

    PubMed Central

    Daly, Seth M.; Hall, Pamela R.; Bayles, Kenneth W.

    2014-01-01

    During a screen of the Nebraska Transposon Mutant Library, we identified 71 mutations in the Staphylococcus aureus genome that altered hemolysis on blood agar medium. Although many of these mutations disrupted genes known to affect the production of alpha-hemolysin, two of them were associated with an apparent operon, designated vfrAB, that had not been characterized previously. Interestingly, a ΔvfrB mutant exhibited only minor effects on the transcription of the hla gene, encoding alpha-hemolysin, when grown in broth, as well as on RNAIII, a posttranscriptional regulatory RNA important for alpha-hemolysin translation, suggesting that VfrB may function at the posttranscriptional level. Indeed, a ΔvfrB mutant had increased aur and sspAB protease expression under these conditions. However, disruption of the known secreted proteases in the ΔvfrB mutant did not restore hemolytic activity in the ΔvfrB mutant on blood agar. Further analysis revealed that, in contrast to the minor effects of VfrB on hla transcription when strains were cultured in liquid media, the level of hla transcription was decreased 50-fold in the absence of VfrB on solid media. These results demonstrate that while VfrB represses protease expression when strains are grown in broth, hla regulation is highly responsive to factors associated with growth on solid media. Intriguingly, the ΔvfrB mutant displayed increased pathogenesis in a model of S. aureus dermonecrosis, further highlighting the complexity of VfrB-dependent virulence regulation. The results of this study describe a phenotype associated with a class of highly conserved yet uncharacterized proteins found in Gram-positive bacteria, and they shed new light on the regulation of virulence factors necessary for S. aureus pathogenesis. PMID:24549328

  7. Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones.

    PubMed

    Shanley, Lynne; Lear, Marissa; Davidson, Scott; Ross, Ruth; MacKenzie, Alasdair

    2011-02-04

    The neuropeptide substance-P (SP) is expressed from the TAC1 gene in sensory neurones where it acts as a key modulator of neurogenic inflammation. The promoter of TAC1 (TAC1prom) plays a central role in the regulation of the TAC1 gene but requires the presence of a second regulatory element; ECR2, to support TAC1 expression in sensory neurones and to respond appropriately to signalling pathways such as MAPkinases and noxious induction by capsaicin. We examined whether the effect of capsaicin on ECR2-TAC1prom activity in larger diameter neurones was cell autonomous or non- cell autonomous. We demonstrate that TRPV1 is not expressed in all the same cells as SP following capsaicin induction suggesting the presence of a non-cell autonomous mechanism for TAC1 up-regulation following capsaicin induction. In addition, we demonstrate that induction of SP and ECR1-TAC1prom activity in these larger diameter neurones can be induced by potassium depolarisation suggesting that, in addition to capsaicin induction, transgene activity may be modulated by voltage gated calcium channels. Furthermore, we show that NK1 is expressed in all SP- expressing cells after capsaicin induction and that an agonist of NK1 can activate both SP and the transgene in larger diameter neurones. These observations suggest the presence of an autocrine loop that controls the expression of the TAC1 promoter in sensory neurones. In contrast, induction of the TAC1 promoter by LPS was not dependent on ECR2 and did not occur in large diameter neurones. These studies demonstrate the diversity of mechanisms modulating the activity of the TAC1 promoter and provide novel directions for the development of new anti-inflammatory therapies.

  8. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome

    PubMed Central

    DeKelver, Russell C.; Choi, Vivian M.; Moehle, Erica A.; Paschon, David E.; Hockemeyer, Dirk; Meijsing, Sebastiaan H.; Sancak, Yasemin; Cui, Xiaoxia; Steine, Eveline J.; Miller, Jeffrey C.; Tam, Phillip; Bartsevich, Victor V.; Meng, Xiangdong; Rupniewski, Igor; Gopalan, Sunita M.; Sun, Helena C.; Pitz, Kathleen J.; Rock, Jeremy M.; Zhang, Lei; Davis, Gregory D.; Rebar, Edward J.; Cheeseman, Iain M.; Yamamoto, Keith R.; Sabatini, David M.; Jaenisch, Rudolf; Gregory, Philip D.; Urnov, Fyodor D.

    2010-01-01

    Isogenic settings are routine in model organisms, yet remain elusive for genetic experiments on human cells. We describe the use of designed zinc finger nucleases (ZFNs) for efficient transgenesis without drug selection into the PPP1R12C gene, a “safe harbor” locus known as AAVS1. ZFNs enable targeted transgenesis at a frequency of up to 15% following transient transfection of both transformed and primary human cells, including fibroblasts and hES cells. When added to this locus, transgenes such as expression cassettes for shRNAs, small-molecule-responsive cDNA expression cassettes, and reporter constructs, exhibit consistent expression and sustained function over 50 cell generations. By avoiding random integration and drug selection, this method allows bona fide isogenic settings for high-throughput functional genomics, proteomics, and regulatory DNA analysis in essentially any transformed human cell type and in primary cells. PMID:20508142

  9. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome.

    PubMed

    DeKelver, Russell C; Choi, Vivian M; Moehle, Erica A; Paschon, David E; Hockemeyer, Dirk; Meijsing, Sebastiaan H; Sancak, Yasemin; Cui, Xiaoxia; Steine, Eveline J; Miller, Jeffrey C; Tam, Phillip; Bartsevich, Victor V; Meng, Xiangdong; Rupniewski, Igor; Gopalan, Sunita M; Sun, Helena C; Pitz, Kathleen J; Rock, Jeremy M; Zhang, Lei; Davis, Gregory D; Rebar, Edward J; Cheeseman, Iain M; Yamamoto, Keith R; Sabatini, David M; Jaenisch, Rudolf; Gregory, Philip D; Urnov, Fyodor D

    2010-08-01

    Isogenic settings are routine in model organisms, yet remain elusive for genetic experiments on human cells. We describe the use of designed zinc finger nucleases (ZFNs) for efficient transgenesis without drug selection into the PPP1R12C gene, a "safe harbor" locus known as AAVS1. ZFNs enable targeted transgenesis at a frequency of up to 15% following transient transfection of both transformed and primary human cells, including fibroblasts and hES cells. When added to this locus, transgenes such as expression cassettes for shRNAs, small-molecule-responsive cDNA expression cassettes, and reporter constructs, exhibit consistent expression and sustained function over 50 cell generations. By avoiding random integration and drug selection, this method allows bona fide isogenic settings for high-throughput functional genomics, proteomics, and regulatory DNA analysis in essentially any transformed human cell type and in primary cells.

  10. Distribution, evolution, and diversity of retrotransposons at the flamenco locus reflect the regulatory properties of piRNA clusters

    PubMed Central

    Zanni, Vanessa; Eymery, Angéline; Coiffet, Michael; Zytnicki, Matthias; Luyten, Isabelle; Quesneville, Hadi; Vaury, Chantal; Jensen, Silke

    2013-01-01

    Most of our understanding of Drosophila heterochromatin structure and evolution has come from the annotation of heterochromatin from the isogenic y; cn bw sp strain. However, almost nothing is known about the heterochromatin’s structural dynamics and evolution. Here, we focus on a 180-kb heterochromatic locus producing Piwi-interacting RNAs (piRNA cluster), the flamenco (flam) locus, known to be responsible for the control of at least three transposable elements (TEs). We report its detailed structure in three different Drosophila lines chosen according to their capacity to repress or not to repress the expression of two retrotransposons named ZAM and Idefix, and we show that they display high structural diversity. Numerous rearrangements due to homologous and nonhomologous recombination, deletions and segmental duplications, and loss and gain of TEs are diverse sources of active genomic variation at this locus. Notably, we evidence a correlation between the presence of ZAM and Idefix in this piRNA cluster and their silencing. They are absent from flam in the strain where they are derepressed. We show that, unexpectedly, more than half of the flam locus results from recent TE insertions and that most of the elements concerned are prone to horizontal transfer between species of the melanogaster subgroup. We build a model showing how such high and constant dynamics of a piRNA master locus open the way to continual emergence of new patterns of piRNA biogenesis leading to changes in the level of transposition control. PMID:24248389

  11. Distribution, evolution, and diversity of retrotransposons at the flamenco locus reflect the regulatory properties of piRNA clusters.

    PubMed

    Zanni, Vanessa; Eymery, Angéline; Coiffet, Michael; Zytnicki, Matthias; Luyten, Isabelle; Quesneville, Hadi; Vaury, Chantal; Jensen, Silke

    2013-12-03

    Most of our understanding of Drosophila heterochromatin structure and evolution has come from the annotation of heterochromatin from the isogenic y; cn bw sp strain. However, almost nothing is known about the heterochromatin's structural dynamics and evolution. Here, we focus on a 180-kb heterochromatic locus producing Piwi-interacting RNAs (piRNA cluster), the flamenco (flam) locus, known to be responsible for the control of at least three transposable elements (TEs). We report its detailed structure in three different Drosophila lines chosen according to their capacity to repress or not to repress the expression of two retrotransposons named ZAM and Idefix, and we show that they display high structural diversity. Numerous rearrangements due to homologous and nonhomologous recombination, deletions and segmental duplications, and loss and gain of TEs are diverse sources of active genomic variation at this locus. Notably, we evidence a correlation between the presence of ZAM and Idefix in this piRNA cluster and their silencing. They are absent from flam in the strain where they are derepressed. We show that, unexpectedly, more than half of the flam locus results from recent TE insertions and that most of the elements concerned are prone to horizontal transfer between species of the melanogaster subgroup. We build a model showing how such high and constant dynamics of a piRNA master locus open the way to continual emergence of new patterns of piRNA biogenesis leading to changes in the level of transposition control.

  12. A cloned regulatory gene of Streptomyces lividans can suppress the pigment deficiency phenotype of different developmental mutants.

    PubMed Central

    Stein, D; Cohen, S N

    1989-01-01

    We report here the cloning of a Streptomyces lividans gene that when introduced on a multicopy plasmid vector reversed the pigment deficiency phenotype of several distinct mutants blocked in development, pigment production, or both. Although this gene was shown by restriction enzyme analysis to be similar to a previously cloned afsB-complementing gene of Streptomyces coelicolor, we show that it does not correspond to the S. coelicolor chromosomal locus designated afsB. Thus, the cloned locus, which we propose to rename afsR, appears to complement the AfsB- phenotype by pleiotropic regulatory effects. Images PMID:2703474

  13. [Gene networks that regulate secondary metabolism in actinomycetes: pleiotropic regulators].

    PubMed

    Rabyk, M V; Ostash, B O; Fedorenko, V O

    2014-01-01

    Current advances in the research and practical applications of pleiotropic regulatory genes for antibiotic production in actinomycetes are reviewed. The basic regulatory mechanisms found in these bacteria are outlined. Examples described in the review show the importance of the manipulation of regulatory systems that affect the synthesis of antibiotics for the metabolic engineering of the actinomycetes. Also, the study of these genes is the basis for the development of genetic engineering approaches towards the induction of "cryptic" part of the actinomycetes secondary metabolome, which capacity for production of biologically active compounds is much bigger than the diversity of antibiotics underpinned by traditional microbiological screening. Besides the practical problems, the study of regulatory genes for antibiotic biosynthesis will provide insights into the process of evolution of complex regulatory systems that coordinate the expression of gene operons, clusters and regulons, involved in the control of secondary metabolism and morphogenesis of actinomycetes.

  14. Genomic matrix attachment region and chromosome conformation capture quantitative real time PCR assays identify novel putative regulatory elements at the imprinted Dlk1/Gtl2 locus.

    PubMed

    Braem, Caroline; Recolin, Bénédicte; Rancourt, Rebecca C; Angiolini, Christopher; Barthès, Pauline; Branchu, Priscillia; Court, Franck; Cathala, Guy; Ferguson-Smith, Anne C; Forné, Thierry

    2008-07-04

    We previously showed that genomic imprinting regulates matrix attachment region activities at the mouse Igf2 (insulin-like growth factor 2) locus and that these activities are functionally linked to neighboring differentially methylated regions (DMRs). Here, we investigate the similarly structured Dlk1/Gtl2 imprinted domain and show that in the mouse liver, the G/C-rich intergenic germ line-derived DMR, a sequence involved in domain-wide imprinting, is highly retained within the nuclear matrix fraction exclusively on the methylated paternal copy, reflecting its differential function on that chromosome. Therefore, not only "classical" A/T-rich matrix attachment region (MAR) sequences but also other important regulatory DNA elements (such as DMRs) can be recovered from genomic MAR assays following a high salt treatment. Interestingly, the recovery of one A/T-rich sequence (MAR4) from the "nuclear matrix" fraction is strongly correlated with gene expression. We show that this element possesses an intrinsic activity that favors transcription, and using chromosome conformation capture quantitative real time PCR assays, we demonstrate that the MAR4 interacts with the intergenic germ line-derived DMR specifically on the paternal allele but not with the Dlk1/Gtl2 promoters. Altogether, our findings shed a new light on gene regulation at this locus.

  15. Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism

    PubMed Central

    Yang, Nianlan; Baban, Babak; Isales, Carlos M.; Shi, Xing-Ming

    2015-01-01

    Bone marrow is a reservoir for regulatory T (Treg) cells, but how Treg cells are regulated in that environment remains poorly understood. We show that expression of glucocorticoid (GC)-induced leucine zipper (GILZ) in bone marrow mesenchymal lineage cells or bone marrow-derived mesenchymal stem cells (BMSCs) increases the production of Treg cells via a mechanism involving the up-regulation of developmental endothelial locus-1 (Del-1), an endogenous leukocyte-endothelial adhesion inhibitor. We found that the expression of Del-1 is increased ∼4-fold in the bone tissues of GILZ transgenic (Tg) mice, and this increase is coupled with a significant increase in the production of IL-10 (2.80 vs. 0.83) and decrease in the production of IL-6 (0.80 vs. 2.33) and IL-12 (0.25 vs. 1.67). We also show that GILZ-expressing BMSCs present antigen in a way that favors Treg cells. These results indicate that GILZ plays a critical role mediating the crosstalk between BMSCs and Treg in the bone marrow microenvironment. These data, together with our previous findings that overexpression of GILZ in BMSCs antagonizes TNF-α-elicited inflammatory responses, suggest that GILZ plays important roles in bone-immune cell communication and BMSC immune suppressive functions.—Yang, N., Baban, B., Isales, C. M., Shi, X.-M. Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. PMID:26038125

  16. Germline deletion of Igh 3′ regulatory region elements hs5-7 affects B cell specific regulation, rearrangement and insulation of the Igh locus1

    PubMed Central

    Volpi, Sabrina A.; Verma-Gaur, Jiyoti; Hassan, Rabih; Ju, Zhongliang; Roa, Sergio; Chatterjee, Sanjukta; Werling, Uwe; Hou, Harry; Will, Britta; Steidl, Ulrich; Scharff, Matthew; Edelman, Winfried; Feeney, Ann J.; Birshtein, Barbara K.

    2012-01-01

    Regulatory elements located within a ~28 kb region 3′ of the Igh gene cluster (3′ regulatory region, 3′ RR) are required for class switch recombination and for high levels of IgH expression in plasma cells. We previously defined novel DNase I hypersensitive (hs) sites, i.e. hs5-7, immediately downstream of this region. Hs5-7 contains a high density of binding sites for CTCF, a zinc finger protein associated with mammalian insulator activity and is an anchor for interactions with CTCF sites flanking the DH region. To test the function of hs5-7, we have generated mice with an 8 kb deletion encompassing all three hs elements. B cells from hs5-7 KO mice showed a modest increase in expression of the nearest downstream gene. In addition, Igh alleles in hs5-7 KO mice were in a less contracted configuration compared to WT Igh alleles and showed a two-fold increase in the usage of proximal VH7183 gene families. Hs5-7 KO mice were essentially indistinguishable from wild type mice in B cell development, allelic regulation, class switch recombination, and chromosomal looping. We conclude that hs5-7--a high-density CTCF binding region at the 3′ end of the Igh locus--impacts usage of VH regions as far as 500 kb away. PMID:22345664

  17. Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans.

    PubMed Central

    Hahn, Matthew W; Rockman, Matthew V; Soranzo, Nicole; Goldstein, David B; Wray, Gregory A

    2004-01-01

    The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution. PMID:15238535

  18. Effects of degU32(Hy), degQa and degR pleiotropic regulatory genes on the growth and protease fermentation of Bacillus subtilis Ki-2-132.

    PubMed

    Pan, Xue-Feng

    2006-04-01

    Effects of degU32 (Hy), degR genes from Bacillus subtilis 168 and degQa gene from Bacillus amyloliquefaciens on Bacillus subtilis Ki-2-132 cell growth, sporulation and protease fermentation were investigated by introducing these genes into B. subtilis Ki-2-132 chromosome and/or cytoplasm. Although the genes come from different species and strains, they showed pleiotropic effects in B. subtilis Ki-2-132. B. subtilis Ki-2-132degU32 (Hy) showed increased protease production, and when cooperating with degQa either in plasmid or in chromosome, further altered cell growth, increased protease production and affected the spore formation in a glucose and dosage dependent manner. By contrast, degR did not significantly affect the protease productivity in degU32 (Hy) mutant, consisting with that DegR was used to stabilise DegU-phosphate, which in degU32 (Hy) strain no longer further amplify the DegU-phosphate effect.

  19. A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus

    PubMed Central

    Beccari, Leonardo; Yakushiji-Kaminatsui, Nayuta; Woltering, Joost M.; Necsulea, Anamaria; Lonfat, Nicolas; Rodríguez-Carballo, Eddie; Mascrez, Benedicte; Yamamoto, Shiori; Kuroiwa, Atsushi

    2016-01-01

    During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition. PMID:27198226

  20. Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence

    PubMed Central

    Larsen, Inna; Craven, Mark; Brandt, Curtis R.

    2016-01-01

    Herpes simplex virus type 1 causes mucocutaneous lesions, and is the leading cause of infectious blindness in the United States. Animal studies have shown that the severity of HSV-1 ocular disease is influenced by three main factors; innate immunity, host immune response and viral strain. We previously showed that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) resulted in recombinants that exhibit a range of disease phenotypes from severe to avirulent, suggesting epistatic interactions were involved. The goal of this study was to develop a quantitative trait locus (QTL) analysis of HSV-1 ocular virulence determinants and to identify virulence associated SNPs. Blepharitis and stromal keratitis quantitative scores were characterized for 40 OD4:CJ994 recombinants. Viral titers in the eye were also measured. Virulence quantitative trait locus mapping (vQTLmap) was performed using the Lasso, Random Forest, and Ridge regression methods to identify significant phenotypically meaningful regions for each ocular disease parameter. The most predictive Ridge regression model identified several phenotypically meaningful SNPs for blepharitis and stromal keratitis. Notably, phenotypically meaningful nonsynonymous variations were detected in the UL24, UL29 (ICP8), UL41 (VHS), UL53 (gK), UL54 (ICP27), UL56, ICP4, US1 (ICP22), US3 and gG genes. Network analysis revealed that many of these variations were in HSV-1 regulatory networks and viral genes that affect innate immunity. Several genes previously implicated in virulence were identified, validating this approach, while other genes were novel. Several novel polymorphisms were also identified in these genes. This approach provides a framework that will be useful for identifying virulence genes in other pathogenic viruses, as well as epistatic effects that affect HSV-1 ocular virulence. PMID:26962864

  1. The function of the conserved regulatory element within the second intron of the mammalian Csf1r locus.

    PubMed

    Sauter, Kristin A; Bouhlel, M Amine; O'Neal, Julie; Sester, David P; Tagoh, Hiromi; Ingram, Richard M; Pridans, Clare; Bonifer, Constanze; Hume, David A

    2013-01-01

    The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.

  2. The Function of the Conserved Regulatory Element within the Second Intron of the Mammalian Csf1r Locus

    PubMed Central

    O’Neal, Julie; Sester, David P.; Tagoh, Hiromi; Ingram, Richard M.; Pridans, Clare; Bonifer, Constanze; Hume, David A.

    2013-01-01

    The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element. PMID:23383005

  3. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus.

    PubMed

    Feng, Yongqiang; Arvey, Aaron; Chinen, Takatoshi; van der Veeken, Joris; Gasteiger, Georg; Rudensky, Alexander Y

    2014-08-14

    In multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. The locus of evolution: evo devo and the genetics of adaptation.

    PubMed

    Hoekstra, Hopi E; Coyne, Jerry A

    2007-05-01

    An important tenet of evolutionary developmental biology ("evo devo") is that adaptive mutations affecting morphology are more likely to occur in the cis-regulatory regions than in the protein-coding regions of genes. This argument rests on two claims: (1) the modular nature of cis-regulatory elements largely frees them from deleterious pleiotropic effects, and (2) a growing body of empirical evidence appears to support the predominant role of gene regulatory change in adaptation, especially morphological adaptation. Here we discuss and critique these assertions. We first show that there is no theoretical or empirical basis for the evo devo contention that adaptations involving morphology evolve by genetic mechanisms different from those involving physiology and other traits. In addition, some forms of protein evolution can avoid the negative consequences of pleiotropy, most notably via gene duplication. In light of evo devo claims, we then examine the substantial data on the genetic basis of adaptation from both genome-wide surveys and single-locus studies. Genomic studies lend little support to the cis-regulatory theory: many of these have detected adaptation in protein-coding regions, including transcription factors, whereas few have examined regulatory regions. Turning to single-locus studies, we note that the most widely cited examples of adaptive cis-regulatory mutations focus on trait loss rather than gain, and none have yet pinpointed an evolved regulatory site. In contrast, there are many studies that have both identified structural mutations and functionally verified their contribution to adaptation and speciation. Neither the theoretical arguments nor the data from nature, then, support the claim for a predominance of cis-regulatory mutations in evolution. Although this claim may be true, it is at best premature. Adaptation and speciation probably proceed through a combination of cis-regulatory and structural mutations, with a substantial contribution of

  5. Molecular architecture of the regulatory Locus sae of Staphylococcus aureus and its impact on expression of virulence factors.

    PubMed

    Steinhuber, Andrea; Goerke, Christiane; Bayer, Manfred G; Döring, Gerd; Wolz, Christiane

    2003-11-01

    We characterized the sae operon, a global regulator for virulence gene expression in Staphylococcus aureus. A Tn917 sae mutant was obtained by screening a Tn917 library of the agr mutant ISP479Mu for clones with altered hemolytic activity. Sequence analysis of the sae operon revealed two additional open reading frames (ORFs) (ORF3 and ORF4) upstream of the two-component regulatory genes saeR and saeS. Four overlapping sae-specific transcripts (T1 to T4) were detected by Northern blot analysis, and the transcriptional initiation points were mapped by primer extension analysis. The T1, T2, and T3 mRNAs are probably terminated at the same stem-loop sequence downstream of saeS. The T1 message (3.1 kb) initiates upstream of ORF4, T2 (2.4 kb) initiates upstream of ORF3, and T3 (2.0 kb) initiates in front of saeR. T4 (0.7 kb) represents a monocistronic mRNA encompassing ORF4 only. sae-specific transcripts were detectable in all of the 40 different clinical S. aureus isolates investigated. Transcript levels were at maximum during the post-exponential growth phase. The sae mutant showed a significantly reduced rate of invasion of human endothelial cells, consistent with diminished transcription and expression of fnbA. The expression of type 5 capsular polysaccharide is activated in the sae mutant of strain Newman, as shown by immunofluorescence and promoter-reporter fusion experiments. In summary, the sae operon constitutes a four-component regulator system which acts on virulence gene expression in S. aureus.

  6. Pleiotropic Analysis of Lung Cancer and Blood Triglycerides.

    PubMed

    Zuber, Verena; Marconett, Crystal N; Shi, Jianxin; Hua, Xing; Wheeler, William; Yang, Chenchen; Song, Lei; Dale, Anders M; Laplana, Marina; Risch, Angela; Witoelar, Aree; Thompson, Wesley K; Schork, Andrew J; Bettella, Francesco; Wang, Yunpeng; Djurovic, Srdjan; Zhou, Beiyun; Borok, Zea; van der Heijden, Henricus F M; de Graaf, Jacqueline; Swinkels, Dorine; Aben, Katja K; McKay, James; Hung, Rayjean J; Bikeböller, Heike; Stevens, Victoria L; Albanes, Demetrius; Caporaso, Neil E; Han, Younghun; Wei, Yongyue; Panadero, Maria Angeles; Mayordomo, Jose I; Christiani, David C; Kiemeney, Lambertus; Andreassen, Ole A; Houlston, Richard; Amos, Christopher I; Chatterjee, Nilanjan; Laird-Offringa, Ite A; Mills, Ian G; Landi, Maria Teresa

    2016-12-01

    Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.

  7. Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus.

    PubMed

    Fogarty, Marie P; Cannon, Maren E; Vadlamudi, Swarooparani; Gaulton, Kyle J; Mohlke, Karen L

    2014-09-01

    Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3'UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.

  8. Spatially differentiated expression of quadruplicated green-sensitive RH2 opsin genes in zebrafish is determined by proximal regulatory regions and gene order to the locus control region.

    PubMed

    Tsujimura, Taro; Masuda, Ryoko; Ashino, Ryuichi; Kawamura, Shoji

    2015-11-04

    Fish are remarkably diverse in repertoires of visual opsins by gene duplications. Differentiation of their spatiotemporal expression patterns and absorption spectra enables fine-tuning of feature detection in spectrally distinct regions of the visual field during ontogeny. Zebrafish have quadruplicated green-sensitive (RH2) opsin genes in tandem (RH2-1, -2, -3, -4), which are expressed in the short member of the double cones (SDC). The shortest wavelength RH2 subtype (RH2-1) is expressed in the central to dorsal area of the adult retina. The second shortest wave subtype (RH2-2) is expressed overlapping with RH2-1 but extending outside of it. The second longest wave subtype (RH2-3) is expressed surrounding the RH2-2 area, and the longest wave subtype (RH2-4) is expressed outside of the RH2-3 area broadly occupying the ventral area. Expression of the four RH2 genes in SDC requires a single enhancer (RH2-LCR), but the mechanism of their spatial differentiation remains elusive. Functional comparison of the RH2-LCR with its counterpart in medaka revealed that the regulatory role of the RH2-LCR in SDC-specific expression is evolutionarily conserved. By combining the RH2-LCR and the proximal upstream region of each RH2 gene with fluorescent protein reporters, we show that the RH2-LCR and the RH2-3 proximal regulatory region confer no spatial selectivity of expression in the retina. But those of RH2-1, -2 and -4 are capable of inducing spatial differentiation of expression. Furthermore, by analyzing transgenic fish with a series of arrays consisting of the RH2-LCR and multiple upstream regions of the RH2 genes in different orders, we show that a gene expression pattern related to an upstream region is greatly influenced by another flanking upstream region in a relative position-dependent manner. The zebrafish RH2 genes except RH2-3 acquired differential cis-elements in the proximal upstream regions to specify the differential expression patterns. The input from these

  9. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

    NASA Astrophysics Data System (ADS)

    Law, Philip J.; Sud, Amit; Mitchell, Jonathan S.; Henrion, Marc; Orlando, Giulia; Lenive, Oleg; Broderick, Peter; Speedy, Helen E.; Johnson, David C.; Kaiser, Martin; Weinhold, Niels; Cooke, Rosie; Sunter, Nicola J.; Jackson, Graham H.; Summerfield, Geoffrey; Harris, Robert J.; Pettitt, Andrew R.; Allsup, David J.; Carmichael, Jonathan; Bailey, James R.; Pratt, Guy; Rahman, Thahira; Pepper, Chris; Fegan, Chris; von Strandmann, Elke Pogge; Engert, Andreas; Försti, Asta; Chen, Bowang; Filho, Miguel Inacio Da Silva; Thomsen, Hauke; Hoffmann, Per; Noethen, Markus M.; Eisele, Lewin; Jöckel, Karl-Heinz; Allan, James M.; Swerdlow, Anthony J.; Goldschmidt, Hartmut; Catovsky, Daniel; Morgan, Gareth J.; Hemminki, Kari; Houlston, Richard S.

    2017-01-01

    B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10‑9) with opposing effects between CLL (P = 1.97 × 10‑8) and HL (P = 3.31 × 10‑3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10‑12) was associated with increased CLL and HL risk (P = 4.68 × 10‑12), and reduced MM risk (P = 1.12 × 10‑2), and Gly70 in HLA-DQB1 (P = 3.15 × 10‑10) showed opposing effects between CLL (P = 3.52 × 10‑3) and HL (P = 3.41 × 10‑9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

  10. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

    PubMed Central

    Law, Philip J.; Sud, Amit; Mitchell, Jonathan S.; Henrion, Marc; Orlando, Giulia; Lenive, Oleg; Broderick, Peter; Speedy, Helen E.; Johnson, David C.; Kaiser, Martin; Weinhold, Niels; Cooke, Rosie; Sunter, Nicola J.; Jackson, Graham H.; Summerfield, Geoffrey; Harris, Robert J.; Pettitt, Andrew R.; Allsup, David J.; Carmichael, Jonathan; Bailey, James R.; Pratt, Guy; Rahman, Thahira; Pepper, Chris; Fegan, Chris; von Strandmann, Elke Pogge; Engert, Andreas; Försti, Asta; Chen, Bowang; Filho, Miguel Inacio da Silva; Thomsen, Hauke; Hoffmann, Per; Noethen, Markus M.; Eisele, Lewin; Jöckel, Karl-Heinz; Allan, James M.; Swerdlow, Anthony J.; Goldschmidt, Hartmut; Catovsky, Daniel; Morgan, Gareth J.; Hemminki, Kari; Houlston, Richard S.

    2017-01-01

    B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10−9) with opposing effects between CLL (P = 1.97 × 10−8) and HL (P = 3.31 × 10−3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10−12) was associated with increased CLL and HL risk (P = 4.68 × 10−12), and reduced MM risk (P = 1.12 × 10−2), and Gly70 in HLA-DQB1 (P = 3.15 × 10−10) showed opposing effects between CLL (P = 3.52 × 10−3) and HL (P = 3.41 × 10−9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs. PMID:28112199

  11. Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression.

    PubMed

    Jones, Bart G; Penkert, Rhiannon R; Xu, Beisi; Fan, Yiping; Neale, Geoff; Gearhart, Patricia J; Hurwitz, Julia L

    2016-09-01

    Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ERα-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the JH cluster to Cδ, with peaks in Eμ and Sμ sites. Additional peaks of ERα binding were coincident with hs1,2 and hs4 sites in the 3' regulatory region (3'RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease.

  12. [Statins and their pleiotropic effects].

    PubMed

    Galus, Ryszard; Zandecki, Łukasz; Jóźwiak, Jarosław; Włodarski, Krzysztof

    2008-06-01

    Statins are well-established and effective drugs in the treatment of hyperlipidemias and coronary heart disease. However the effects of statins extend beyond their lipid-lowering actions, due to their capacity to inhibit prenylation of some intracellular regulatory proteins. Recent studies have shown that statins could modulate inflammantory response, improve endothelial function, exert antiarrhytmic properties, have beneficial effects on renal function and bone tissue. Statins may exert effect in the treament and prevention of dementia and some autoimmune disorders. Although statins therapy is generally well-tolerated, sometimes they lead to objective adverse effects, mainly in muscular system. Combination therapy with fibrates, coenzyme Q and other substances may increase and even extend therapeutic effects of statins. Further studies will help to clarify the clinical role of statins.

  13. Homologous Elements hs3a and hs3b in the 3′ Regulatory Region of the Murine Immunoglobulin Heavy Chain (Igh) Locus Are Both Dispensable for Class-switch Recombination*

    PubMed Central

    Yan, Yi; Pieretti, Joyce; Ju, Zhongliang; Wei, Shiniu; Christin, John R.; Bah, Fatmata; Birshtein, Barbara K.; Eckhardt, Laurel A.

    2011-01-01

    Immunoglobulin heavy chain (IgH) genes are formed, tested, and modified to yield diverse, specific, and high affinity antibody responses to antigen. The processes involved must be regulated, however, to avoid unintended damage to chromosomes. The 3′ regulatory region of the Igh locus plays a major role in regulating class-switch recombination (CSR), the process by which antibody effector functions are modified during an immune response. Loss of all known enhancer-like elements in this region dramatically impairs CSR, but individual element deletions have no effect on this process. In the present study, we explored the hypothesis that an underlying functional redundancy in the homologous elements hs3a and hs3b was masking the importance of either element to CSR. Several transgenic mouse lines were generated, each carrying a bacterial artificial chromosome transgene that mimicked Igh locus structure but in which hs3a was missing and hs3b was flanked by loxP sites. Matings to Cyclization Recombination Enzyme-expressing mice established “pairs” of lines that differed only in the presence or absence of hs3b. Remarkably, CSR remained robust in the absence of both hs3a and hs3b, suggesting that the remaining two elements of the 3′ regulatory region, hs1.2 and hs4, although individually dispensable for CSR, are, together, sufficient to support CSR. PMID:21673112

  14. Heparin: 100 years of pleiotropic effects.

    PubMed

    Paschoa, Adilson Ferraz

    2016-05-01

    Heparin is a glycosaminoglycan with anticoagulant properties and antiinflammatory effects. The discovery of heparin approaches its 100th year and its antiinflammatory properties still draws much attention and anticipation to new possibilities of use and the likelihood of developing heparin-like drugs that lacked the anticoagulation effects. It is known that heparins limit the embolization and the extension of the thrombus, although they do not promote its complete lysis in most cases. The complexity and pleiotropic characteristics of these glycosaminoglycans still challenge science, to the point in which approaches hitherto unusual appear repeatedly in the literature. New indications, accompanied by longtime consecrated others, dismantle the idea of an outdated medication and create high expectations for the near future. The objective of this review is to analyze the pleiotropic effects of heparin and its use in several diseases, highlighting its safety and effectiveness.

  15. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

    PubMed

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward L; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan K; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Buchanan, Daniel D; Casey, Graham; Conti, David V; Edlund, Christopher K; Gallinger, Steven; Haile, Robert W; Jenkins, Mark; Le Marchand, Loïc; Li, Li; Lindor, Noralene M; Schmit, Stephanie L; Thibodeau, Stephen N; Woods, Michael O; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

    2016-09-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

  16. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

    PubMed Central

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fred; Schildkraut, Joellen; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Olama, Ali Amin Al; Berndt, Sonja I; Giovannucci, Edward; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter; Goode, Ellen L.; Permuth, Jennifer; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma’en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. PMID:27197191

  17. Molecular characterization of the mouse agouti locus.

    PubMed

    Bultman, S J; Michaud, E J; Woychik, R P

    1992-12-24

    The agouti (a) locus acts within the microenvironment of the hair follicle to regulate coat color pigmentation in the mouse. We have characterized a gene encoding a novel 131 amino acid protein that we propose is the one gene associated with the agouti locus. This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy. In addition, we found that the pleiotropic effects associated with the lethal yellow (Ay) mutation, which include pronounced obesity, diabetes, and the development of neoplasms, are accompanied by deregulated overexpression of the agouti gene in numerous tissues of the adult animal.

  18. The pleiotropic effects of the seed germination inhibitor germostatin.

    PubMed

    Ye, Yajin; Zhao, Yang

    2016-01-01

    Seed dormancy and germination are the most important adaptive traits of seed plants, which control the germination in a proper space and time. Internal genetic factors together with environmental cues govern seed dormancy and germination. Abscisic acid (ABA), a key phytohormone induces seed dormancy and inhibits seed germination through its molecular genetic signaling network responding the seed inherent physiological and environmental factors. Recently, auxin has been shown to be another phytohormone that induces seed dormancy. We have recently shown that germonstatin (GS), a small synthetic molecule identified by high through-put chemical genetic screenings, inhibits seed germination through up-regulating auxin signaling and inducing auxin biosynthesis. GERMOSTATIN RESISTANCE LOCUS 1 (GSR1) encodes a plant homeodomain (PHD) finger protein and is responsible for GS seed germination inhibition. Its knockdown mutant gsr1 displays decreased dormancy. In this report, we show that GS is not an ABA analog and provided 2 other GS-resistant mutants related to the chemical's function in seed germination inhibition other than gsr1, suggesting that GS may have pleiotropic effects through targeting different pathway governing seed germination.

  19. Effect of tomato pleiotropic ripening mutations on flavour volatile biosynthesis.

    PubMed

    Kovács, Katalin; Fray, Rupert G; Tikunov, Yury; Graham, Neil; Bradley, Glyn; Seymour, Graham B; Bovy, Arnaud G; Grierson, Donald

    2009-05-01

    Ripening is a tightly controlled and developmentally regulated process involving networks of genes, and metabolites that result in dramatic changes in fruit colour, texture and flavour. Molecular and genetic analysis in tomato has revealed a series of regulatory genes involved in fruit development and ripening, including MADS box and SPB box transcription factors and genes involved in ethylene synthesis, signalling and response. Volatile metabolites represent a significant part of the plant metabolome, playing an important role in plant signalling, defence strategies and probably in regulatory mechanisms. They also play an important role in fruit quality. In order to acquire a better insight into the biochemical and genetic control of flavour compound generation and links between these metabolites and the central regulators of ripening, five pleiotropic mutant tomato lines were subjected to volatile metabolite profiling in comparison with wild-type Ailsa Craig. One hundred and seventeen volatile compounds were identified and quantified using SPME (Solid Phase Microextraction) headspace extraction followed by Gas Chromatography-Mass Spectrometry (GC-MS) and the data were subjected to multivariate comparative analysis. We find that the different mutants each produce distinct volatile profiles during ripening. Through principal component analysis the volatiles most dramatically affected are those derived from fatty-acids. The results are consistent with the suggestion that specific isoforms of lipoxygenase located in the plastids and the enzymes that provide precursors and downstream metabolites play a key role in determining volatile composition.

  20. Hfq and three Hfq-dependent small regulatory RNAs-MgrR, RyhB and McaS-coregulate the locus of enterocyte effacement in enteropathogenic Escherichia coli.

    PubMed

    Bhatt, Shantanu; Egan, Marisa; Ramirez, Jasmine; Xander, Christian; Jenkins, Valerie; Muche, Sarah; El-Fenej, Jihad; Palmer, Jamie; Mason, Elisabeth; Storm, Elizabeth; Buerkert, Thomas

    2017-02-01

    Enteropathogenic Escherichia coli (EPEC) is a significant cause of infantile diarrhea and death in developing countries. The pathogenicity island locus of enterocyte effacement (LEE) is essential for EPEC to cause diarrhea. Besides EPEC, the LEE is also present in other gastrointestinal pathogens, most notably enterohemorrhagic E. coli (EHEC). Whereas transcriptional control of the LEE has been meticulously examined, posttranscriptional regulation, including the role of Hfq-dependent small RNAs, remains undercharacterized. However, the past few years have witnessed a surge in the identification of riboregulators of the LEE in EHEC. Contrastingly, the posttranscriptional regulatory landscape of EPEC remains cryptic. Here we demonstrate that the RNA-chaperone Hfq represses the LEE of EPEC by targeting the 5' untranslated leader region of grlR in the grlRA mRNA. Three conserved small regulatory RNAs (sRNAs)-MgrR, RyhB and McaS-are involved in the Hfq-dependent regulation of grlRA MgrR and RyhB exert their effects by directly base-pairing to the 5' region of grlR Whereas MgrR selectively represses grlR but activates grlA, RyhB represses gene expression from the entire grlRA transcript. Meanwhile, McaS appears to target the grlRA mRNA indirectly. Thus, our results provide the first definitive evidence that implicates multiple sRNAs in regulating the LEE and the resulting virulence of EPEC.

  1. A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus

    PubMed Central

    Bossis, I; Voutetakis, A; Matyakhina, L; Pack, S; Abu-Asab, M; Bourdeau, I; Griffin, K; Courcoutsakis, N; Stergiopoulos, S; Batista, D; Tsokos, M; Stratakis, C

    2004-01-01

    Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIAi locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas. PMID:15286154

  2. Integration of Elf-4 into stem/progenitor and erythroid regulatory networks through locus-wide chromatin studies coupled with in vivo functional validation.

    PubMed

    Smith, Aileen M; Calero-Nieto, Fernando J; Schütte, Judith; Kinston, Sarah; Timms, Richard T; Wilson, Nicola K; Hannah, Rebecca L; Landry, Josette-Renee; Göttgens, Berthold

    2012-02-01

    The ETS transcription factor Elf-4 is an important regulator of hematopoietic stem cell (HSC) and T cell homeostasis. To gain insights into the transcriptional circuitry within which Elf-4 operates, we used comparative sequence analysis coupled with chromatin immunoprecipitation (ChIP) with microarray technology (ChIP-chip) assays for specific chromatin marks to identify three promoters and two enhancers active in hematopoietic and endothelial cell lines. Comprehensive functional validation of each of these regulatory regions in transgenic mouse embryos identified a tissue-specific enhancer (-10E) that displayed activity in fetal liver, dorsal aorta, vitelline vessels, yolk sac, and heart. Integration of a ChIP-sequencing (ChIP-Seq) data set for 10 key stem cell transcription factors showed Pu.1, Fli-1, and Erg were bound to the -10E element, and mutation of three highly conserved ETS sites within the enhancer abolished its activity. Finally, the transcriptional repressor Gfi1b was found to bind to and repress one of the Elf-4 promoters (-30P), and we show that this repression of Elf-4 is important for the maturation of primary fetal liver erythroid cells. Taken together, our results provide a comprehensive overview of the transcriptional control of Elf-4 within the hematopoietic system and, thus, integrate Elf-4 into the wider transcriptional regulatory networks that govern hematopoietic development.

  3. Curcumin: a pleiotropic phytonutrient in diabetic complications.

    PubMed

    Jeenger, Manish Kumar; Shrivastava, Shweta; Yerra, Veera Ganesh; Naidu, V G M; Ramakrishna, Sistla; Kumar, Ashutosh

    2015-02-01

    Curcumin is the major polyphenolic constituent of an indigenous herb, Curcuma longa, found to have a wide range of applications right from its kitchen use as a spicy ingredient to therapeutic and medicinal applications in various diseases. Curcumin has been identified to have a plethora of biologic and pharmacologic properties owing to its antioxidant and anti-inflammatory activities. This pleiotropic regulation of redox balance of cell and inflammation might be the basis of curcumin's beneficial activities in various pathologic conditions including diabetic complications. This review summarizes various in vitro, in vivo studies done on curcumin and its therapeutic utility in diabetic micro-vascular complications. This review also emphasizes the importance of curcumin in addition to the existing therapeutic modalities in diabetic complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. The pleiotropic effects of angiotensin receptor blockers.

    PubMed

    Chrysant, Steven G; Chrysant, George S

    2006-04-01

    The angiotensin receptor blockers (ARBs) are very effective and safe antihypertensive drugs. They exert their antihypertensive effect through blockage of the angiotensin II, type 1 receptor and quite possibly through stimulation by angiotensin II of the unoccupied type 2 receptor. Besides hypertension, the ARBs have been found recently to be of value in the treatment of heart failure and diabetic nephropathy. In addition, ARBs have emerged lately as being very effective and perhaps superior to other antihypertensive drugs in the prevention of de novo or recurrent strokes. Other actions that may account for their stroke-protective effects include their antiatherogenic, antidiabetic, antiplatelet aggregating, hypouricemic, and atrial antifibrillatory actions. All these actions make the ARBs a true pleiotropic class of drugs. Each of the foregoing effects will be discussed briefly in this concise review.

  5. Myopia and intelligence: a pleiotropic relationship?

    PubMed

    Cohn, S J; Cohn, C M; Jensen, A R

    1988-09-01

    The well-established association between myopia and superior intelligence in the general population was investigated in a group of intellectually gifted children and their less gifted full siblings to determine whether the relationship of myopia to psychometric intelligence is consistent with the hypothesis of pleiotropy, i.e., both characteristics are affected by the same gene or set of genes. Failure to find a difference in degree of myopia, assessed as a metric variable, between intellectually gifted and nongifted siblings would contradict pleiotropy. A variety of possible causal pathways, both genetic and environmental, have been hypothesized in the literature to explain the relationship between intelligence and myopia, and these still cannot be ruled out. It is theoretically noteworthy, however, in view of the independent evidence for the considerable heritability of both intelligence and myopia, that the highly significant gifted-nongifted sibling difference in myopia found in the present study is consistent with the hypothesis that intelligence and myopia are related pleiotropically.

  6. Genetic Relatedness of Clostridium difficile Isolates from Various Origins Determined by Triple-Locus Sequence Analysis Based on Toxin Regulatory Genes tcdC, tcdR, and cdtR▿

    PubMed Central

    Bouvet, Philippe J. M.; Popoff, Michel R.

    2008-01-01

    A triple-locus nucleotide sequence analysis based on toxin regulatory genes tcdC, tcdR and cdtR was initiated to assess the sequence variability of these genes among Clostridium difficile isolates and to study the genetic relatedness between isolates. A preliminary investigation of the variability of the tcdC gene was done with 57 clinical and veterinary isolates. Twenty-three isolates representing nine main clusters were selected for tcdC, tcdR, and cdtR analysis. The numbers of alleles found for tcdC, tcdR and cdtR were nine, six, and five, respectively. All strains possessed the cdtR gene except toxin A-negative toxin B-positive variants. All but one binary toxin CDT-positive isolate harbored a deletion (>1 bp) in the tcdC gene. The combined analyses of the three genes allowed us to distinguish five lineages correlated with the different types of deletion in tcdC, i.e., 18 bp (associated or not with a deletion at position 117), 36 bp, 39 bp, and 54 bp, and with the wild-type tcdC (no deletion). The tcdR and tcdC genes, though located within the same pathogenicity locus, were found to have evolved separately. Coevolution of the three genes was noted only with strains harboring a 39-bp or a 54-bp deletion in tcdC that formed two homogeneous, separate divergent clusters. Our study supported the existence of the known clones (PCR ribotype 027 isolates and toxin A-negative toxin B-positive C. difficile variants) and evidence for clonality of isolates with a 39-bp deletion (toxinotype V, PCR ribotype 078) that are frequently isolated worldwide from human infections and from food animals. PMID:18832125

  7. Pleiotropic regulation of mitochondrial function by adipose triglyceride lipase-mediated lipolysis☆

    PubMed Central

    Kratky, Dagmar; Obrowsky, Sascha; Kolb, Dagmar; Radovic, Branislav

    2014-01-01

    Lipolysis is defined as the catabolism of triacylglycerols (TGs) stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for TG catabolism in most cells and tissues. This review focuses on recent advances in understanding the (patho)physiological impact due to defective lipolysis by ATGL deficiency on mitochondrial (dys)function. Depending on the type of cells and tissues investigated, absence of ATGL has pleiotropic roles in mitochondrial function. PMID:23827855

  8. Pleiotropic genes for metabolic syndrome and inflammation.

    PubMed

    Kraja, Aldi T; Chasman, Daniel I; North, Kari E; Reiner, Alexander P; Yanek, Lisa R; Kilpeläinen, Tuomas O; Smith, Jennifer A; Dehghan, Abbas; Dupuis, Josée; Johnson, Andrew D; Feitosa, Mary F; Tekola-Ayele, Fasil; Chu, Audrey Y; Nolte, Ilja M; Dastani, Zari; Morris, Andrew; Pendergrass, Sarah A; Sun, Yan V; Ritchie, Marylyn D; Vaez, Ahmad; Lin, Honghuang; Ligthart, Symen; Marullo, Letizia; Rohde, Rebecca; Shao, Yaming; Ziegler, Mark A; Im, Hae Kyung; Schnabel, Renate B; Jørgensen, Torben; Jørgensen, Marit E; Hansen, Torben; Pedersen, Oluf; Stolk, Ronald P; Snieder, Harold; Hofman, Albert; Uitterlinden, Andre G; Franco, Oscar H; Ikram, M Arfan; Richards, J Brent; Rotimi, Charles; Wilson, James G; Lange, Leslie; Ganesh, Santhi K; Nalls, Mike; Rasmussen-Torvik, Laura J; Pankow, James S; Coresh, Josef; Tang, Weihong; Linda Kao, W H; Boerwinkle, Eric; Morrison, Alanna C; Ridker, Paul M; Becker, Diane M; Rotter, Jerome I; Kardia, Sharon L R; Loos, Ruth J F; Larson, Martin G; Hsu, Yi-Hsiang; Province, Michael A; Tracy, Russell; Voight, Benjamin F; Vaidya, Dhananjay; O'Donnell, Christopher J; Benjamin, Emelia J; Alizadeh, Behrooz Z; Prokopenko, Inga; Meigs, James B; Borecki, Ingrid B

    2014-08-01

    Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic

  9. Pleiotropic genes for metabolic syndrome and inflammation

    PubMed Central

    Kraja, Aldi T.; Chasman, Daniel I.; North, Kari E.; Reiner, Alexander P.; Yanek, Lisa R.; Kilpeläinen, Tuomas O.; Smith, Jennifer A.; Dehghan, Abbas; Dupuis, Josée; Johnson, Andrew D.; Feitosa, Mary F.; Tekola-Ayele, Fasil; Chu, Audrey Y.; Nolte, Ilja M.; Dastani, Zari; Morris, Andrew; Pendergrass, Sarah A.; Sun, Yan V.; Ritchie, Marylyn D.; Vaez, Ahmad; Lin, Honghuang; Ligthart, Symen; Marullo, Letizia; Rohde, Rebecca; Shao, Yaming; Ziegler, Mark A.; Im, Hae Kyung; Schnabel, Renate B.; Jørgensen, Torben; Jørgensen, Marit E.; Hansen, Torben; Pedersen, Oluf; Stolk, Ronald P.; Snieder, Harold; Hofman, Albert; Uitterlinden, Andre G.; Franco, Oscar H.; Ikram, M. Arfan; Richards, J. Brent; Rotimi, Charles; Wilson, James G.; Lange, Leslie; Ganesh, Santhi K.; Nalls, Mike; Rasmussen-Torvik, Laura J.; Pankow, James S.; Coresh, Josef; Tang, Weihong; Kao, W.H. Linda; Boerwinkle, Eric; Morrison, Alanna C.; Ridker, Paul M.; Becker, Diane M.; Rotter, Jerome I.; Kardia, Sharon L.R.; Loos, Ruth J.F.; Larson, Martin G.; Hsu, Yi-Hsiang; Province, Michael A.; Tracy, Russell; Voight, Benjamin F.; Vaidya, Dhananjay; O’Donnell, Christopher; Benjamin, Emelia J.; Alizadeh, Behrooz Z.; Prokopenko, Inga; Meigs, James B.; Borecki, Ingrid B.

    2014-01-01

    Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic

  10. Interleukin (IL)-25: Pleiotropic roles in asthma.

    PubMed

    Yao, Xiujuan; Sun, Yongchang; Wang, Wei; Sun, Ying

    2016-05-01

    IL-25, also named IL-17E, is a distinct member of the IL-17 cytokine family, which can promote and augment T helper type 2 (Th2) responses locally or systemically. Growing evidence from experimental and clinical studies indicates that the expression of IL-25 and its cognate receptor, IL-17RB/RA, is markedly upregulated in asthmatic conditions. It has also been found that IL-25 induces not only typical eosinophilic inflammation and airway hyperresponsiveness (AHR), but also airway remodelling, manifested by goblet cell hyperplasia, subepithelial collagen deposition and angiogenesis. This review will focus on the discovery, cellular origins and targets of IL-25, and try to update current animal and human studies elucidating the roles of IL-25 in asthma. We conclude that although IL-25 is a pleiotropic cytokine, it may only play its dominant role in a certain specific asthmatic endotype, named 'IL-25 high' phenotype. Thus, targeting IL-25 or its receptor might selectively benefit some subgroups with asthma. Furthermore, the major IL-25 producing as well as responsive cells in the changeable milieu of asthma should be assessed in the future.

  11. Statins: pleiotropic regulators of cardiovascular redox state.

    PubMed

    Antoniades, Charalambos; Channon, Keith M

    2014-03-10

    Lipid-lowering treatment with statins is one of the most effective therapeutic strategies in cardiovascular medicine because they reduce cardiovascular risk in both primary and secondary prevention. Despite the well-established links between low-density lipoprotein and cardiovascular risk, the clinical benefit from statin treatment is not fully explained by their lipid-lowering potential. A number of pleiotropic effects of statins have been described over the past decade, and their ability to suppress global oxidative stress is probably one of the most important mechanisms by which they exert their beneficial effects on the cardiovascular system. In this Forum, there are review articles discussing the molecular mechanisms by which statins modify redox signaling in the vasculature and the heart. They exert direct effects on the vascular wall and the myocardium or indirect by targeting the interactions between the cardiovascular system and adipose tissue or circulating cell types. The review articles in this Forum follow a translational approach and link the molecular mechanisms by which statins modify cardiovascular redox signaling with their clinical benefit in the prevention and treatment of cardiovascular diseases.

  12. Statins: Pleiotropic Regulators of Cardiovascular Redox State

    PubMed Central

    Channon, Keith M.

    2014-01-01

    Abstract Lipid-lowering treatment with statins is one of the most effective therapeutic strategies in cardiovascular medicine because they reduce cardiovascular risk in both primary and secondary prevention. Despite the well-established links between low-density lipoprotein and cardiovascular risk, the clinical benefit from statin treatment is not fully explained by their lipid-lowering potential. A number of pleiotropic effects of statins have been described over the past decade, and their ability to suppress global oxidative stress is probably one of the most important mechanisms by which they exert their beneficial effects on the cardiovascular system. In this Forum, there are review articles discussing the molecular mechanisms by which statins modify redox signaling in the vasculature and the heart. They exert direct effects on the vascular wall and the myocardium or indirect by targeting the interactions between the cardiovascular system and adipose tissue or circulating cell types. The review articles in this Forum follow a translational approach and link the molecular mechanisms by which statins modify cardiovascular redox signaling with their clinical benefit in the prevention and treatment of cardiovascular diseases. Antioxid. Redox Signal. 20, 1195–1197. PMID:24409984

  13. Pleiotropic effects in Eya3 knockout mice

    PubMed Central

    Söker, Torben; Dalke, Claudia; Puk, Oliver; Floss, Thomas; Becker, Lore; Bolle, Ines; Favor, Jack; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Kallnik, Magdalena; Kling, Eva; Moerth, Corinna; Schrewe, Anja; Stigloher, Christian; Topp, Stefanie; Gailus-Durner, Valerie; Naton, Beatrix; Beckers, Johannes; Fuchs, Helmut; Ivandic, Boris; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; Bally-Cuif, Laure; de Angelis, Martin Hrabé; Graw, Jochen

    2008-01-01

    Background In Drosophila, mutations in the gene eyes absent (eya) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understood and no mouse model exists for Eya3. Therefore, we characterized the phenotype of a new Eya3 knockout mouse mutant. Results Expression analysis of Eya3 by in-situ hybridizations and β-Gal-staining of Eya3 mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos. The phenotype of young adult Eya3 mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of Eya3 mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed Nup155 being down regulated in both organs. Conclusion The loss of Eya3 in the mouse has no apparent effect on eye development. The wide-spread expression of Eya3 in mouse and zebrafish embryos is in contrast to the restricted expression pattern in Xenopus embryos. The loss of Eya3 in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of Eya3 function should focus on aging mice. PMID:19102749

  14. A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication

    PubMed Central

    Johnsson, Martin; Gustafson, Ida; Rubin, Carl-Johan; Sahlqvist, Anna-Stina; Jonsson, Kenneth B.; Kerje, Susanne; Ekwall, Olov; Kämpe, Olle; Andersson, Leif; Jensen, Per; Wright, Dominic

    2012-01-01

    Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations. PMID:22956912

  15. High-resolution mapping of the wheat Lr46 pleiotropic rust resistance locus

    USDA-ARS?s Scientific Manuscript database

    Rust diseases are the most important diseases of wheat globally, and genetic resistance is the most effective method for controlling all three rusts. Numerous resistance genes have been characterized and reported. For typical resistance genes, the mechanism of resistance and the basis of race specif...

  16. Characterization of rco-1 of Neurospora crassa, a pleiotropic gene affecting growth and development that encodes a homolog of Tup1 of Saccharomyces cerevisiae.

    PubMed Central

    Yamashiro, C T; Ebbole, D J; Lee, B U; Brown, R E; Bourland, C; Madi, L; Yanofsky, C

    1996-01-01

    The filamentous fungus Neurospora crassa undergoes a well-defined developmental program, conidiation, that culminates in the production of numerous asexual spores, conidia. Several cloned genes, including con-10, are expressed during conidiation but not during mycelial growth. Using a previously described selection strategy, we isolated mutants that express con-10 during mycelial growth. Selection was based on expression of an integrated DNA fragment containing the con-10 promoter-regulatory region followed by the initial segment of the con-10 open reading frame fused in frame with the bacterial hygromycin B phosphotransferase structural gene (con10'-'hph). Resistance to hygromycin results from mutational alterations that allow mycelial expression of the con-10'-'hph gene fusion. A set of drug-resistant mutants were isolated; several of these had abnormal conidiation phenotypes and were trans-acting, i.e., they allowed mycelial expression of the endogenous con-10 gene. Four of these had alterations at a single locus, designated rco-1 (regulation of conidiation). Strains with the rco-1 mutant alleles were aconidial, female sterile, had reduced growth rates, and formed hyphae that coiled in a counterclockwise direction, opposite that of the wild type. The four rco-1 mutants had distinct conidiation morphologies, suggesting that conidiation was blocked at different stages. Wild-type rco-1 was cloned by a novel procedure employing heterokaryon-assisted transformation and ligation-mediated PCR. The predicted RCO1 polypeptide is a homolog of Tup1 of Saccharomyces cerevisiae, a multidomain protein that mediates transcriptional repression of genes concerned with a variety of processes. Like tup1 mutants, null mutants of rco-1 are viable and pleiotropic. A promoter element was identified that could be responsible for RCO1-mediated vegetative repression of con-10 and other conidiation genes. PMID:8887652

  17. Landscape of Pleiotropic Proteins Causing Human Disease: Structural and System Biology Insights.

    PubMed

    Ittisoponpisan, Sirawit; Alhuzimi, Eman; Sternberg, Michael J E; David, Alessia

    2017-03-01

    Pleiotropy is the phenomenon by which the same gene can result in multiple phenotypes. Pleiotropic proteins are emerging as important contributors to rare and common disorders. Nevertheless, little is known on the mechanisms underlying pleiotropy and the characteristic of pleiotropic proteins. We analyzed disease-causing proteins reported in UniProt and observed that 12% are pleiotropic (variants in the same protein cause more than one disease). Pleiotropic proteins were enriched in deleterious and rare variants, but not in common variants. Pleiotropic proteins were more likely to be involved in the pathogenesis of neoplasms, neurological, and circulatory diseases and congenital malformations, whereas non-pleiotropic proteins in endocrine and metabolic disorders. Pleiotropic proteins were more essential and had a higher number of interacting partners compared with non-pleiotropic proteins. Significantly more pleiotropic than non-pleiotropic proteins contained at least one intrinsically long disordered region (P < 0.001). Deleterious variants occurring in structurally disordered regions were more commonly found in pleiotropic, rather than non-pleiotropic proteins. In conclusion, pleiotropic proteins are an important contributor to human disease. They represent a biologically different class of proteins compared with non-pleiotropic proteins and a better understanding of their characteristics and genetic variants can greatly aid in the interpretation of genetic studies and drug design.

  18. Pleiotropic mutations are subject to strong stabilizing selection.

    PubMed

    McGuigan, Katrina; Collet, Julie M; Allen, Scott L; Chenoweth, Stephen F; Blows, Mark W

    2014-07-01

    The assumption that pleiotropic mutations are more deleterious than mutations with more restricted phenotypic effects is an important premise in models of evolution. However, empirical evidence supporting this assumption is limited. Here, we estimated the strength of stabilizing selection on mutations affecting gene expression in male Drosophila serrata. We estimated the mutational variance (VM) and the standing genetic variance (VG) from two well-matched panels of inbred lines: a panel of mutation accumulation (MA) lines derived from a single inbred ancestral line and a panel of inbred lines derived from an outbred population. For 855 gene-expression traits, we estimated the strength of stabilizing selection as s = VM/VG. Selection was observed to be relatively strong, with 17% of traits having s > 0.02, a magnitude typically associated with life-history traits. Randomly assigning expression traits to five-trait sets, we used factor analytic mixed modeling in the MA data set to identify covarying traits that shared pleiotropic mutations. By assigning traits to the same trait sets in the outbred line data set, we then estimated s for the combination of traits affected by pleiotropic mutation. For these pleiotropic combinations, the median s was three times greater than s acting on the individual component traits, and 46% of the pleiotropic trait combinations had s > 0.02. Although our analytical approach was biased toward detecting mutations with relatively large effects, likely overestimating the average strength of selection, our results provide widespread support for the prediction that stronger selection can act against mutations with pleiotropic effects.

  19. Association Between Seed Dormancy and Pericarp Color Is Controlled by a Pleiotropic Gene That Regulates Abscisic Acid and Flavonoid Synthesis in Weedy Red Rice

    PubMed Central

    Gu, Xing-You; Foley, Michael E.; Horvath, David P.; Anderson, James V.; Feng, Jiuhuan; Zhang, Lihua; Mowry, Chase R.; Ye, Heng; Suttle, Jeffrey C.; Kadowaki, Koh-ichi; Chen, Zongxiang

    2011-01-01

    Seed dormancy has been associated with red grain color in cereal crops for a century. The association was linked to qSD7-1/qPC7, a cluster of quantitative trait loci for seed dormancy/pericarp color in weedy red rice. This research delimited qSD7-1/qPC7 to the Os07g11020 or Rc locus encoding a basic helix-loop-helix family transcription factor by intragenic recombinants and provided unambiguous evidence that the association arises from pleiotropy. The pleiotropic gene expressed in early developing seeds promoted expression of key genes for biosynthesis of abscisic acid (ABA), resulting in an increase in accumulation of the dormancy-inducing hormone; activated a conserved network of eight genes for flavonoid biosynthesis to produce the pigments in the lower epidermal cells of the pericarp tissue; and enhanced seed weight. Thus, the pleiotropic locus most likely controls the dormancy and pigment traits by regulating ABA and flavonoid biosynthetic pathways, respectively. The dormancy effect could be eliminated by a heat treatment, but could not be completely overcome by gibberellic acid or physical removal of the seed maternal tissues. The dormancy-enhancing alleles differentiated into two groups basically associated with tropical and temperate ecotypes of weedy rice. Of the pleiotropic effects, seed dormancy could contribute most to the weed adaptation. Pleiotropy prevents the use of the dormancy gene to improve resistance of white pericarp cultivars against pre-harvest sprouting through conventional breeding approaches. PMID:21954164

  20. Pleiotropic Role of the RNA Chaperone Protein Hfq in the Human Pathogen Clostridium difficile

    PubMed Central

    Boudry, P.; Gracia, C.; Monot, M.; Caillet, J.; Saujet, L.; Hajnsdorf, E.; Dupuy, B.; Martin-Verstraete, I.

    2014-01-01

    Clostridium difficile is an emergent human pathogen and the most common cause of nosocomial diarrhea. Our recent data strongly suggest the importance of RNA-based mechanisms for the control of gene expression in C. difficile. In an effort to understand the function of the RNA chaperone protein Hfq, we constructed and characterized an Hfq-depleted strain in C. difficile. Hfq depletion led to a growth defect, morphological changes, an increased sensitivity to stresses, and a better ability to sporulate and to form biofilms. The transcriptome analysis revealed pleiotropic effects of Hfq depletion on gene expression in C. difficile, including genes encoding proteins involved in sporulation, stress response, metabolic pathways, cell wall-associated proteins, transporters, and transcriptional regulators and genes of unknown function. Remarkably, a great number of genes of the regulon dependent on sporulation-specific sigma factor, SigK, were upregulated in the Hfq-depleted strain. The altered accumulation of several sRNAs and interaction of Hfq with selected sRNAs suggest potential involvement of Hfq in these regulatory RNA functions. Altogether, these results suggest the pleiotropic role of Hfq protein in C. difficile physiology, including processes important for the C. difficile infection cycle, and expand our knowledge of Hfq-dependent regulation in Gram-positive bacteria. PMID:24982306

  1. Pleiotropic effects of statins: new therapeutic targets in drug design.

    PubMed

    Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

    2016-07-01

    The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

  2. Ongoing Clinical Trials of the Pleiotropic Effects of Statins

    PubMed Central

    Davignon, Jean; Leiter, Lawrence A

    2005-01-01

    Background The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. Objective To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. Method Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000–2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990–2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins' nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. Results Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer's disease, multiple sclerosis, and stroke (outcomes often overlapped). Conclusion Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients. PMID:17319096

  3. Pleiotropic regulation of mitochondrial function by adipose triglyceride lipase-mediated lipolysis.

    PubMed

    Kratky, Dagmar; Obrowsky, Sascha; Kolb, Dagmar; Radovic, Branislav

    2014-01-01

    Lipolysis is defined as the catabolism of triacylglycerols (TGs) stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for TG catabolism in most cells and tissues. This review focuses on recent advances in understanding the (patho)physiological impact due to defective lipolysis by ATGL deficiency on mitochondrial (dys)function. Depending on the type of cells and tissues investigated, absence of ATGL has pleiotropic roles in mitochondrial function. Copyright © 2013 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  4. How do pleiotropic kinase hubs mediate specific signaling by TNFR superfamily members?

    PubMed Central

    Schröfelbauer, Bärbel; Hoffmann, Alexander

    2012-01-01

    Summary Tumor necrosis factor receptor (TNFR) superfamily members mediate the cellular response to a wide variety of biological inputs. The responses range from cell death, survival, differentiation, proliferation, to the regulation of immunity. All these physiological responses are regulated by a limited number of highly pleiotropic kinases. The fact that the same signaling molecules are involved in transducing signals from TNFR superfamily members that regulate different and even opposing processes raises the question of how their specificity is determined. Regulatory strategies that can contribute to signaling specificity include scaffolding to control kinase specificity, combinatorial use of several signal transducers, and temporal control of signaling. In this review, we discuss these strategies in the context of TNFR superfamily member signaling. PMID:22017429

  5. Pleiotropic functions of catabolite control protein CcpA in Butanol-producing Clostridium acetobutylicum

    PubMed Central

    2012-01-01

    Background Clostridium acetobutylicum has been used to produce butanol in industry. Catabolite control protein A (CcpA), known to mediate carbon catabolite repression (CCR) in low GC gram-positive bacteria, has been identified and characterized in C. acetobutylicum by our previous work (Ren, C. et al. 2010, Metab Eng 12:446–54). To further dissect its regulatory function in C. acetobutylicum, CcpA was investigated using DNA microarray followed by phenotypic, genetic and biochemical validation. Results CcpA controls not only genes in carbon metabolism, but also those genes in solvent production and sporulation of the life cycle in C. acetobutylicum: i) CcpA directly repressed transcription of genes related to transport and metabolism of non-preferred carbon sources such as d-xylose and l-arabinose, and activated expression of genes responsible for d-glucose PTS system; ii) CcpA is involved in positive regulation of the key solventogenic operon sol (adhE1-ctfA-ctfB) and negative regulation of acidogenic gene bukII; and iii) transcriptional alterations were observed for several sporulation-related genes upon ccpA inactivation, which may account for the lower sporulation efficiency in the mutant, suggesting CcpA may be necessary for efficient sporulation of C. acetobutylicum, an important trait adversely affecting the solvent productivity. Conclusions This study provided insights to the pleiotropic functions that CcpA displayed in butanol-producing C. acetobutylicum. The information could be valuable for further dissecting its pleiotropic regulatory mechanism in C. acetobutylicum, and for genetic modification in order to obtain more effective butanol-producing Clostridium strains. PMID:22846451

  6. Pleiotropic functions of catabolite control protein CcpA in Butanol-producing Clostridium acetobutylicum.

    PubMed

    Ren, Cong; Gu, Yang; Wu, Yan; Zhang, Weiwen; Yang, Chen; Yang, Sheng; Jiang, Weihong

    2012-07-30

    Clostridium acetobutylicum has been used to produce butanol in industry. Catabolite control protein A (CcpA), known to mediate carbon catabolite repression (CCR) in low GC gram-positive bacteria, has been identified and characterized in C. acetobutylicum by our previous work (Ren, C. et al. 2010, Metab Eng 12:446-54). To further dissect its regulatory function in C. acetobutylicum, CcpA was investigated using DNA microarray followed by phenotypic, genetic and biochemical validation. CcpA controls not only genes in carbon metabolism, but also those genes in solvent production and sporulation of the life cycle in C. acetobutylicum: i) CcpA directly repressed transcription of genes related to transport and metabolism of non-preferred carbon sources such as d-xylose and l-arabinose, and activated expression of genes responsible for d-glucose PTS system; ii) CcpA is involved in positive regulation of the key solventogenic operon sol (adhE1-ctfA-ctfB) and negative regulation of acidogenic gene bukII; and iii) transcriptional alterations were observed for several sporulation-related genes upon ccpA inactivation, which may account for the lower sporulation efficiency in the mutant, suggesting CcpA may be necessary for efficient sporulation of C. acetobutylicum, an important trait adversely affecting the solvent productivity. This study provided insights to the pleiotropic functions that CcpA displayed in butanol-producing C. acetobutylicum. The information could be valuable for further dissecting its pleiotropic regulatory mechanism in C. acetobutylicum, and for genetic modification in order to obtain more effective butanol-producing Clostridium strains.

  7. The sae locus of Staphylococcus aureus controls exoprotein synthesis at the transcriptional level.

    PubMed

    Giraudo, A T; Cheung, A L; Nagel, R

    1997-07-01

    Agr and sar are known regulatory loci of Staphylococcus aureus that control the production of several extracellular and cell-wall-associated proteins. A pleiotropic insertional mutation in S. aureus, designated sae, that leads to the production of drastically diminished levels of alpha- and beta-hemolysins and coagulase and slightly reduced levels of protein A has been described. The study of the expression of the genes coding for these exoproteins in the sae::Tn551 mutant (carried out in this work by Northern blot analyses) revealed that the genes for alpha- and beta-hemolysins (hla and hlb) and coagulase (coa) are not transcribed and that the gene for protein A (spa) is transcribed at a somewhat reduced level. These results indicate that the sae locus regulates these exoprotein genes at the transcriptional level. Northern blot analyses also show that the sae mutation does not affect the expression of agr or sar regulatory loci. An sae::Tn551 agr::tetM double mutant has been phenotypically characterized as producing reduced or null levels of alpha-, beta-, and delta-hemolysins, coagulase, and high levels of protein A. Northern blot analyses carried out in this work with the double mutant revealed that hla, hlb, hld, and coa genes are not transcribed, while spa is transcribed at high levels. The fact that coa is not expressed in the sae agr mutant, as in the sae parental strain, while spa is expressed at the high levels characteristic of the agr parental strain, suggests that sae and agr interact in a complex way in the control of the expression of the genes of several exoproteins.

  8. Functional confirmation of PLAG1 as the candidate causative gene underlying major pleiotropic effects on body weight and milk characteristics

    PubMed Central

    Fink, Tania; Tiplady, Kathryn; Lopdell, Thomas; Johnson, Thomas; Snell, Russell G.; Spelman, Richard J.; Davis, Stephen R.; Littlejohn, Mathew D.

    2017-01-01

    A major pleiotropic quantitative trait locus (QTL) located at ~25 Mbp on bovine chromosome 14 affects a myriad of growth and developmental traits in Bos taurus and indicus breeds. These QTL have been attributed to two functional variants in the bidirectional promoter of PLAG1 and CHCHD7. Although PLAG1 is a good candidate for mediating these effects, its role remains uncertain given that these variants are also associated with expression of five additional genes at the broader locus. In the current study, we conducted expression QTL (eQTL) mapping of this region using a large, high depth mammary RNAseq dataset representing 375 lactating cows. Here we show that of the seven previously implicated genes, only PLAG1 and LYN are differentially expressed by QTL genotype, and only PLAG1 bears the same association signature of the growth and body weight QTLs. For the first time, we also report significant association of PLAG1 genotype with milk production traits, including milk fat, volume, and protein yield. Collectively, these data strongly suggest PLAG1 as the causative gene underlying this diverse range of traits, and demonstrate new effects for the locus on lactation phenotypes. PMID:28322319

  9. Pleiotropic regulations of neutrophil receptors response to sepsis.

    PubMed

    Zhang, Huafeng; Sun, Bingwei

    2017-03-01

    Sepsis is a complex clinical condition that causes a high mortality rate worldwide. Numerous studies on the pathophysiology of sepsis have revealed an imbalance in the inflammatory network, thus leading to tissue damage, organ failure, and ultimately death. The impairment of neu-trophil migration is associated with the outcome of sepsis. Literature review was performed on the roles of neutrophil recruitment and neutrophil receptors as pleiotropic regulators during sepsis. Additionally, we systematically classify neutrophil receptors with regard to the neutrophil response during sepsis and discuss the clinical implications of these receptors for the treatment of sepsis. Increasing evidence suggests that there is significant dysfunction in neutrophil recruitment during sepsis, characterized by the failure to migrate to the site of infection. Neutrophil receptors, as pleiotropic regulators, play important roles in the neutrophil response during sepsis. Neutrophil receptors play key roles in chemotactic neutrophil migration and may prove to be suitable targets in future pharmacological therapies for sepsis.

  10. Endothelial progenitor cells: Exploring the pleiotropic effects of statins.

    PubMed

    Sandhu, Kully; Mamas, Mamas; Butler, Robert

    2017-01-26

    Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction, prior to any significant change in lipid profile. Therefore, pleiotropic mechanisms, other than lowering lipid profile alone, must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell (EPC) identification, role in vascular repair, factors affecting EPC numbers, the role of statins in current medical practice and their effects on EPC number.

  11. Endothelial progenitor cells: Exploring the pleiotropic effects of statins

    PubMed Central

    Sandhu, Kully; Mamas, Mamas; Butler, Robert

    2017-01-01

    Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction, prior to any significant change in lipid profile. Therefore, pleiotropic mechanisms, other than lowering lipid profile alone, must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell (EPC) identification, role in vascular repair, factors affecting EPC numbers, the role of statins in current medical practice and their effects on EPC number. PMID:28163831

  12. A natural variant of NAL1, selected in high-yield rice breeding programs, pleiotropically increases photosynthesis rate.

    PubMed

    Takai, Toshiyuki; Adachi, Shunsuke; Taguchi-Shiobara, Fumio; Sanoh-Arai, Yumiko; Iwasawa, Norio; Yoshinaga, Satoshi; Hirose, Sakiko; Taniguchi, Yojiro; Yamanouchi, Utako; Wu, Jianzhong; Matsumoto, Takashi; Sugimoto, Kazuhiko; Kondo, Katsuhiko; Ikka, Takashi; Ando, Tsuyu; Kono, Izumi; Ito, Sachie; Shomura, Ayahiko; Ookawa, Taiichiro; Hirasawa, Tadashi; Yano, Masahiro; Kondo, Motohiko; Yamamoto, Toshio

    2013-01-01

    Improvement of leaf photosynthesis is an important strategy for greater crop productivity. Here we show that the quantitative trait locus GPS (GREEN FOR PHOTOSYNTHESIS) in rice (Oryza sativa L.) controls photosynthesis rate by regulating carboxylation efficiency. Map-based cloning revealed that GPS is identical to NAL1 (NARROW LEAF1), a gene previously reported to control lateral leaf growth. The high-photosynthesis allele of GPS was found to be a partial loss-of-function allele of NAL1. This allele increased mesophyll cell number between vascular bundles, which led to thickened leaves, and it pleiotropically enhanced photosynthesis rate without the detrimental side effects observed in previously identified nal1 mutants, such as dwarf plant stature. Furthermore, pedigree analysis suggested that rice breeders have repeatedly selected the high-photosynthesis allele in high-yield breeding programs. The identification and utilization of NAL1 (GPS) can enhance future high-yield breeding and provides a new strategy for increasing rice productivity.

  13. An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1

    PubMed Central

    Lorberbaum, David S; Ramos, Andrea I; Peterson, Kevin A; Carpenter, Brandon S; Parker, David S; De, Sandip; Hillers, Lauren E; Blake, Victoria M; Nishi, Yuichi; McFarlane, Matthew R; Chiang, Ason CY; Kassis, Judith A; Allen, Benjamin L; McMahon, Andrew P; Barolo, Scott

    2016-01-01

    The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptch1 reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptch1 is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure—one of the oldest cis-regulatory features discovered in animal genomes—explains how patched/Ptch1 can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways. DOI: http://dx.doi.org/10.7554/eLife.13550.001 PMID:27146892

  14. Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity

    PubMed Central

    Sapp, Julie C.; Nishimura, Darryl; Johnston, Jennifer J.; Stone, Edwin M.; Héon, Elise; Sheffield, Val C.; Biesecker, Leslie G.

    2011-01-01

    Purpose Bardet-Biedl syndrome is a pleiotropic multiple anomaly syndrome inherited in an autosomal recessive pattern. It is now known that this disorder has locus heterogeneity, with causative mutations identified in as many as 14 genes. The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with BBS. Methods Mutation data from 187 probands affected with BBS were used. The authors counted the relative proportion of families with mutations at each of ten loci and estimated locus-specific carrier rates for mutations using Hardy-Weinberg principles and an aggregate population frequency of 1/100,000 for the phenotype. Locus-specific recurrence risks were calculated for relatives of an affected proband. Results Locus-specific carrier frequencies range from 1/250 to 1/2200, and the risks for an offspring of the sibling of an affected individual range from 1/1,500 to 1/13,000. The estimate of this risk derived under a locus homogeneity model is 1/960. Conclusion Variation of recurrence risks of this magnitude may have implications for genetic counseling of families with affected individuals, in particular about prenatal testing and other reproductive options. Similar analyses to determine locus-specific carrier frequencies for other phenotypes with significant locus heterogeneity may yield similarly relevant results. PMID:20949666

  15. Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity.

    PubMed

    Sapp, Julie C; Nishimura, Darryl; Johnston, Jennifer J; Stone, Edwin M; Héon, Elise; Sheffield, Val C; Biesecker, Leslie G

    2010-10-01

    Bardet-Biedl syndrome is a pleiotropic multiple anomaly syndrome inherited in an autosomal recessive pattern. It is now known that this disorder has locus heterogeneity, with causative mutations identified in as many as 14 genes. The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with Bardet-Biedl syndrome. Mutation data from 187 probands affected with Bardet-Biedl syndrome were used. The authors counted the relative proportion of families with mutations at each of 10 loci and estimated locus-specific carrier rates for mutations using Hardy-Weinberg principles and an aggregate population frequency of 1/100,000 for the phenotype. Locus-specific recurrence risks were calculated for relatives of an affected proband. Locus-specific carrier frequencies range from 1/250 to 1/2200, and the risks for an offspring of the sibling of an affected individual range from 1/1,500 to 1/13,000. The estimate of this risk derived under a locus homogeneity model is 1/960. Variation of recurrence risks of this magnitude may have implications for genetic counseling of families with affected individuals, in particular about prenatal testing and other reproductive options. Similar analyses to determine locus-specific carrier frequencies for other phenotypes with significant locus heterogeneity may yield similarly relevant results.

  16. Image simulation using LOCUS

    SciTech Connect

    Strachan, J.D.; Roberts, J.A.

    1989-09-01

    The LOCUS data base program has been used to simulate images and to solve simple equations. This has been accomplished by making each record (which normally would represent a data entry)represent sequenced or random number pairs.

  17. A pleiotropic interaction between vision loss and hypermelanism in Astyanax mexicanus cave x surface hybrids.

    PubMed

    Gross, Joshua B; Powers, Amanda K; Davis, Erin M; Kaplan, Shane A

    2016-06-30

    Cave-dwelling animals evolve various traits as a consequence of life in darkness. Constructive traits (e.g., enhanced non-visual sensory systems) presumably arise under strong selective pressures. The mechanism(s) driving regression of features, however, are not well understood. Quantitative trait locus (QTL) analyses in Astyanax mexicanus Pachón cave x surface hybrids revealed phenotypic effects associated with vision and pigmentation loss. Vision QTL were uniformly associated with reductions in the homozygous cave condition, however pigmentation QTL demonstrated mixed phenotypic effects. This implied pigmentation might be lost through both selective and neutral forces. Alternatively, in this report, we examined if a pleiotropic interaction may exist between vision and pigmentation since vision loss has been shown to result in darker skin in other fish and amphibian model systems. We discovered that certain members of Pachón x surface pedigrees are significantly darker than surface-dwelling fish. All of these "hypermelanic" individuals demonstrated severe visual system malformations suggesting they may be blind. A vision-mediated behavioral assay revealed that these fish, in stark contrast to surface fish, behaved the same as blind cavefish. Further, hypermelanic melanophores were larger and more dendritic in morphology compared to surface fish melanophores. However, hypermelanic melanophores responded normally to melanin-concentrating hormone suggesting darkening stemmed from vision loss, rather than a defect in pigment cell function. Finally, a number of genomic regions were coordinately associated with both reduced vision and increased pigmentation. This work suggests hypermelanism in hybrid Astyanax results from blindness. This finding provides an alternative explanation for phenotypic effect studies of pigmentation QTL as stemming (at least in part) from environmental, rather than exclusively genetic, interactions between two regressive phenotypes. Further

  18. Pleiotropic Effects of Statins in the Perioperative Setting

    PubMed Central

    Galyfos, George; Sianou, Argyri; Filis, Konstantinos

    2017-01-01

    Statins belong to a specific group of drugs that have been described for their ability to control hyperlipidemia as well as for other pleiotropic effects such as improving vascular endothelial function, inhibition of oxidative stress pathways, and anti-inflammatory actions. Accumulating clinical evidence strongly suggests that statins also have a beneficial effect on perioperative morbidity and mortality. Therefore, this review aims to present all recent and pooled data on statin treatment in the perioperative setting as well as to highlight considerations regarding their indications and therapeutic application. PMID:28074822

  19. Pleiotropic effects of niacin: Current possibilities for its clinical use.

    PubMed

    Zeman, Miroslav; Vecka, Marek; Perlík, František; Staňková, Barbora; Hromádka, Robert; Tvrzická, Eva; Širc, Jakub; Hrib, Jakub; Žák, Aleš

    2016-12-01

    Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin's role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.

  20. MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.

    PubMed

    Lin, J; Teo, S; Lam, D H; Jeyaseelan, K; Wang, S

    2012-10-04

    Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.

  1. DasR is a pleiotropic regulator required for antibiotic production, pigment biosynthesis, and morphological development in Saccharopolyspora erythraea.

    PubMed

    Liao, Cheng-Heng; Xu, Ya; Rigali, Sébastien; Ye, Bang-Ce

    2015-12-01

    The GntR-family transcription regulator, DasR, was previously identified as pleiotropic, controlling the primary amino sugar N-acetylglucosamine (GlcNAc) and chitin metabolism in Saccharopolyspora erythraea and Streptomyces coelicolor. Due to the remarkable regulatory impact of DasR on antibiotic production and development in the model strain of S. coelicolor, we here identified and characterized the role of DasR to secondary metabolite production and morphological development in industrial erythromycin-producing S. erythraea. The physiological studies have shown that a constructed deletion of dasR in S. erythraea resulted in antibiotic, pigment, and aerial hyphae production deficit in a nutrient-rich condition. DNA microarray assay, combined with quantitative real-time reverse transcription PCR (qRT-PCR), confirmed these results by showing the downregulation of the genes relating to secondary metabolite production in the dasR null mutant. Notably, electrophoretic mobility shift assays (EMSA) showed DasR as being the first identified regulator that directly regulates the pigment biosynthesis rpp gene cluster. In addition, further studies indicated that GlcNAc, the major nutrient signal of DasR-responsed regulation, blocked secondary metabolite production and morphological development. The effects of GlcNAc were shown to be caused by DasR mediation. These findings demonstrated that DasR is an important pleiotropic regulator for both secondary metabolism and morphological development in S. erythraea, providing new insights for the genetic engineering of S. erythraea with increased erythromycin production.

  2. Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus.

    PubMed

    Bastepe, M; Pincus, J E; Sugimoto, T; Tojo, K; Kanatani, M; Azuma, Y; Kruse, K; Rosenbloom, A L; Koshiyama, H; Jüppner, H

    2001-06-01

    Pseudohypoparathyroidism type Ib (PHP-Ib) is a paternally imprinted disorder which maps to a region on chromosome 20q13.3 that comprises GNAS1 at its telomeric boundary. Exon A/B of this gene was recently shown to display a loss of methylation in several PHP-Ib patients. In nine unrelated PHP-Ib kindreds, in whom haplotype analysis and mode of inheritance provided no evidence against linkage to this chromosomal region, we confirmed lack of exon A/B methylation for affected individuals, while unaffected carriers showed no epigenetic abnormality at this locus. However, affected individuals in one kindred (Y2) displayed additional methylation defects involving exons NESP55, AS and XL, and unaffected carriers in this family showed an abnormal methylation at exon NESP55, but not at other exons. Taken together, current evidence thus suggests that distinct mutations within or close to GNAS1 can lead to PHP-Ib and the associated epigenetic changes. To further delineate the telomeric boundary of the PHP-Ib locus, the previously reported kindred F, in which patient F-V/51 is recombinant within GNAS1, was investigated with several new markers and direct nucleotide sequence analysis. These studies revealed that F-V/51 remains recombinant at a single nucleotide polymorphism (SNP) located 1.2 kb upstream of XL. No heterozygous mutation was identified between exon XL and an SNP approximately 8 kb upstream of NESP55, where this affected individual becomes linked, suggesting that the genetic defect responsible for parathyroid hormone resistance in kindred F, and probably other PHP-Ib patients, is located >or=56 kb centromeric of the abnormally methylated exon A/B. A region upstream of the known coding exons of GNAS1 is therefore predicted to exert, presumably through imprinting of exon A/B, long-range effects on G(s)alpha expression.

  3. The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism.

    PubMed

    Egido, Jesús; Martínez-Castelao, Alberto; Bover, Jordi; Praga, Manuel; Torregrosa, José Vicente; Fernández-Giráldez, Elvira; Solozábal, Carlos

    2016-01-01

    Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD.

  4. Pleiotropic vascular protective effects of statins in perioperative medicine.

    PubMed

    Fang, Shin-Yuan; Roan, Jun-Neng; Luo, Chwan-Yau; Tsai, Yu-Chuan; Lam, Chen-Fuh

    2013-09-01

    3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the most commonly prescribed agents for controlling hyperlipidemia. Apart from their lipid-lowering property, statins are well known for their pleiotropic effects, such as improvement of vascular endothelial dysfunction, attenuation of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle proliferation, and modulation of procoagulant activity and platelet function. The vasculo-protective effect of statins is mainly mediated by inhibition of the mevalonate pathway and oxidized low-density lipoprotein generation, thereby enhancing the biosynthesis of endothelium-derived nitric oxide. Accumulating clinical evidence strongly suggests that administration of statins reduces overall mortality, the development myocardial infarction and atrial fibrillation, and length of hospital stay after a major cardiac/noncardiac surgery. This review updates the clinical pharmacology and therapeutic applications of statins during major operations, and highlights the anesthesia considerations for perioperative statin therapy.

  5. Pleiotropic aspartate taxis and serine taxis mutants of Escherichia coli.

    PubMed

    Reader, R W; Tso, W W; Springer, M S; Goy, M F; Adler, J

    1979-04-01

    Mutants that at one time were thought to be specifically defective in taxis toward aspartate and related amino acids (tar mutants) or specifically defective in taxis toward serine and related amino acids (tar mutants) are now shown to be pleiotropic in their defects. The tar mutants also lack taxis toward maltose and away from Co2+ and Ni2+. The tsr mutants are altered in their response to a variety of repellents. Double mutants (tar tsr) fail in nearly all chemotactic responses. The tar and tsr mutants provide evidence for two complementary, converging pathways of information flow: certain chemoreceptors feed information into the tar pathway and others into the tsr pathway. The tar and tsr products have been shown to be two different sets of methylated proteins.

  6. Genetic Dissection of a Genomic Region with Pleiotropic Effects on Domestication Traits in Maize Reveals Multiple Linked QTL

    PubMed Central

    Lemmon, Zachary H.; Doebley, John F.

    2014-01-01

    The domesticated crop maize and its wild progenitor, teosinte, have been used in numerous experiments to investigate the nature of divergent morphologies. This study examines a poorly understood region on the fifth chromosome of maize associated with a number of traits under selection during domestication, using a quantitative trait locus (QTL) mapping population specific to the fifth chromosome. In contrast with other major domestication loci in maize where large-effect, highly pleiotropic, single genes are responsible for phenotypic effects, our study found the region on chromosome five fractionates into multiple-QTL regions, none with singularly large effects. The smallest 1.5-LOD support interval for a QTL contained 54 genes, one of which was a MADS MIKCC transcription factor, a family of proteins implicated in many developmental programs. We also used simulated trait data sets to investigate the power of our mapping population to identify QTL for which there is a single underlying causal gene. This analysis showed that while QTL for traits controlled by single genes can be accurately mapped, our population design can detect no more than ∼4.5 QTL per trait even when there are 100 causal genes. Thus when a trait is controlled by ≥5 genes in the simulated data, the number of detected QTL can represent a simplification of the underlying causative factors. Our results show how a QTL region with effects on several domestication traits may be due to multiple linked QTL of small effect as opposed to a single gene with large and pleiotropic effects. PMID:24950893

  7. Evidence for pleiotropic factors in genetics of the musculoskeletal system

    PubMed Central

    Karasik, David; Kiel, Douglas P.

    2016-01-01

    There are both theoretical and empirical underpinnings that provide evidence that the musculoskeletal system develops, functions, and ages as a whole. Thus, the risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Both bone loss (osteoporosis) and muscle wasting (sarcopenia) are the two sides of the same coin, an involution of the musculoskeletal system. Skeletal loads are dominated by muscle action; both bone and muscle share environmental, endocrine and paracrine influences. Muscle also has an endocrine function by producing bioactive molecules, which can contribute to homeostatic regulation of both bone and muscle. It also becomes clear that bone and muscle share genetic determinants; therefore the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. The aim of this review is to provide an additional evidence for existence of the tight genetic co-regulation of muscles and bones, starting early in development and still evident in aging. Recently, important papers were published, including those dealing with the cellular mechanisms and anatomic substrate of bone mechanosensitivity. Further evidence has emerged suggesting that the relationship between skeletal muscle and bone parameters extends beyond the general paradigm of bone responses to mechanical loading. We provide insights into several pathways and single genes, which apparently have a biologically plausible pleiotropic effect on both bones and muscles; the list is continuing to grow. Understanding the crosstalk between muscles and bones will translate into a conceptual framework aimed at studying the pleiotropic genetic relationships in the etiology of complex musculoskeletal disease. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both

  8. Network properties of human disease genes with pleiotropic effects

    PubMed Central

    2010-01-01

    Background The ability of a gene to cause a disease is known to be associated with the topological position of its protein product in the molecular interaction network. Pleiotropy, in human genetic diseases, refers to the ability of different mutations within the same gene to cause different pathological effects. Here, we hypothesized that the ability of human disease genes to cause pleiotropic effects would be associated with their network properties. Results Shared genes, with pleiotropic effects, were more central than specific genes that were associated with one disease, in the protein interaction network. Furthermore, shared genes associated with phenotypically divergent diseases (phenodiv genes) were more central than those associated with phenotypically similar diseases. Shared genes had a higher number of disease gene interactors compared to specific genes, implying higher likelihood of finding a novel disease gene in their network neighborhood. Shared genes had a relatively restricted tissue co-expression with interactors, contrary to specific genes. This could be a function of shared genes leading to pleiotropy. Essential and phenodiv genes had comparable connectivities and hence we investigated for differences in network attributes conferring lethality and pleiotropy, respectively. Essential and phenodiv genes were found to be intra-modular and inter-modular hubs with the former being highly co-expressed with their interactors contrary to the latter. Essential genes were predominantly nuclear proteins with transcriptional regulation activities while phenodiv genes were cytoplasmic proteins involved in signal transduction. Conclusion The properties of a disease gene in molecular interaction network determine its role in manifesting different and divergent diseases. PMID:20525321

  9. Bayesian Methods for Multivariate Modeling of Pleiotropic SNP Associations and Genetic Risk Prediction

    PubMed Central

    Hartley, Stephen W.; Monti, Stefano; Liu, Ching-Ti; Steinberg, Martin H.; Sebastiani, Paola

    2012-01-01

    Genome-wide association studies (GWAS) have identified numerous associations between genetic loci and individual phenotypes; however, relatively few GWAS have attempted to detect pleiotropic associations, in which loci are simultaneously associated with multiple distinct phenotypes. We show that pleiotropic associations can be directly modeled via the construction of simple Bayesian networks, and that these models can be applied to produce single or ensembles of Bayesian classifiers that leverage pleiotropy to improve genetic risk prediction. The proposed method includes two phases: (1) Bayesian model comparison, to identify Single-Nucleotide Polymorphisms (SNPs) associated with one or more traits; and (2) cross-validation feature selection, in which a final set of SNPs is selected to optimize prediction. To demonstrate the capabilities and limitations of the method, a total of 1600 case-control GWAS datasets with two dichotomous phenotypes were simulated under 16 scenarios, varying the association strengths of causal SNPs, the size of the discovery sets, the balance between cases and controls, and the number of pleiotropic causal SNPs. Across the 16 scenarios, prediction accuracy varied from 90 to 50%. In the 14 scenarios that included pleiotropically associated SNPs, the pleiotropic model search and prediction methods consistently outperformed the naive model search and prediction. In the two scenarios in which there were no true pleiotropic SNPs, the differences between the pleiotropic and naive model searches were minimal. To further evaluate the method on real data, a discovery set of 1071 sickle cell disease (SCD) patients was used to search for pleiotropic associations between cerebral vascular accidents and fetal hemoglobin level. Classification was performed on a smaller validation set of 352 SCD patients, and showed that the inclusion of pleiotropic SNPs may slightly improve prediction, although the difference was not statistically significant. The

  10. The IGF2 Locus

    USDA-ARS?s Scientific Manuscript database

    Insulin-like growth factor 2 (IGF2) is a peptide hormone regulating various cellular processes such as proliferation and apoptosis. IGF2 is vital to embryo development. The IGF2 locus covers approximately 150-kb genomic region on human chromosome 11, containing two imprinted genes, IGF2 and H19, sha...

  11. Mutations in Barley Row Type Genes Have Pleiotropic Effects on Shoot Branching.

    PubMed

    Liller, Corinna Brit; Neuhaus, René; von Korff, Maria; Koornneef, Maarten; van Esse, Wilma

    2015-01-01

    Cereal crop yield is determined by different yield components such as seed weight, seed number per spike and the tiller number and spikes. Negative correlations between these traits are often attributed to resource limitation. However, recent evidence suggests that the same genes or regulatory modules can regulate both inflorescence branching and tillering. It is therefore important to explore the role of genetic correlations between different yield components in small grain cereals. In this work, we studied pleiotropic effects of row type genes on seed size, seed number per spike, thousand grain weight, and tillering in barley to better understand the genetic correlations between individual yield components. Allelic mutants of nine different row type loci (36 mutants), in the original spring barley varieties Barke, Bonus and Foma and introgressed in the spring barley cultivar Bowman, were phenotyped under greenhouse and outdoor conditions. We identified two main mutant groups characterized by their relationships between seed and tillering parameters. The first group comprises all mutants with an increased number of seeds and significant change in tiller number at early development (group 1a) or reduced tillering only at full maturity (group 1b). Mutants in the second group are characterized by a reduction in seeds per spike and tiller number, thus exhibiting positive correlations between seed and tiller number. Reduced tillering at full maturity (group 1b) is likely due to resource limitations. In contrast, altered tillering at early development (groups 1a and 2) suggests that the same genes or regulatory modules affect inflorescence and shoot branching. Understanding the genetic bases of the trade-offs between these traits is important for the genetic manipulation of individual yield components.

  12. Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

    PubMed Central

    He, Liang; Kernogitski, Yelena; Kulminskaya, Irina; Loika, Yury; Arbeev, Konstantin G.; Loiko, Elena; Bagley, Olivia; Duan, Matt; Yashkin, Arseniy; Ukraintseva, Svetlana V.; Kovtun, Mikhail; Yashin, Anatoliy I.; Kulminski, Alexander M.

    2016-01-01

    Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on

  13. Genotyping of the Q locus in wheat by a simple PCR-RFLP method.

    PubMed

    Asakura, Nobuaki; Mori, Naoki; Nakamura, Chiharu; Ohtsuka, Ichiro

    2009-06-01

    The Q locus located on the long arm of chromosome 5A is a key factor in evolution and widespread cultivation of domesticated wheat. The Q locus pleiotropically affects many agronomically important traits including threshability, glume shape and tenacity, rachis fragility and others. Genotyping of the Q locus based on the complex traits is ambiguous due to their multi-genetic control through interactions with the Q locus. To determine the Q locus genotype of wheat accessions possessing A genome, we developed a method based on polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) analysis. The Q and q alleles were clearly distinguished by PCR-RFLP analysis at six conserved single nucleotide polymorphisms in common wheat and wild and cultivated einkorn, emmer and timopheevi wheat. The Q locus genotype of Triticum sinskajae, which is one of the einkorn wheat species and exhibits free-threshing trait, was determined to be qq as expected. This simple PCR-RLFP-based genotyping method should serve as a useful tool in studying the origin of Q and thus wheat evolution after domestication and the following widespread cultivation.

  14. Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

    PubMed Central

    Guo, Michael H.; Nandakumar, Satish K.; Ulirsch, Jacob C.; Zekavat, Seyedeh M.; Buenrostro, Jason D.; Natarajan, Pradeep; Salem, Rany M.; Chiarle, Roberto; Mitt, Mario; Kals, Mart; Pärn, Kalle; Fischer, Krista; Milani, Lili; Mägi, Reedik; Palta, Priit; Gabriel, Stacey B.; Metspalu, Andres; Lander, Eric S.; Kathiresan, Sekar; Hirschhorn, Joel N.; Esko, Tõnu; Sankaran, Vijay G.

    2017-01-01

    Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance. PMID:28031487

  15. Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

    PubMed

    Guo, Michael H; Nandakumar, Satish K; Ulirsch, Jacob C; Zekavat, Seyedeh M; Buenrostro, Jason D; Natarajan, Pradeep; Salem, Rany M; Chiarle, Roberto; Mitt, Mario; Kals, Mart; Pärn, Kalle; Fischer, Krista; Milani, Lili; Mägi, Reedik; Palta, Priit; Gabriel, Stacey B; Metspalu, Andres; Lander, Eric S; Kathiresan, Sekar; Hirschhorn, Joel N; Esko, Tõnu; Sankaran, Vijay G

    2017-01-17

    Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.

  16. Why Pleiotropic Interventions are Needed for Alzheimer's Disease

    PubMed Central

    Cole, Greg M.

    2010-01-01

    Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of β-amyloid (Aβ) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Aβ production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Aβ peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the “prodromal” period prior to conversion to “mild cognitive impairment (MCI).” Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic

  17. The Cnes2 Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

    PubMed Central

    Shourian, Mitra; Flaczyk, Adam; Angers, Isabelle; Mindt, Barbara C.; Fritz, Jörg H.

    2015-01-01

    The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+ dendritic cells, and CD4+ cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection. PMID:26371125

  18. Fine mapping and candidate gene prediction of a pleiotropic quantitative trait locus for yield-related trait in Zea mays.

    PubMed

    Liu, Ruixiang; Jia, Haitao; Cao, Xiaoliang; Huang, Jun; Li, Feng; Tao, Yongsheng; Qiu, Fazhan; Zheng, Yonglian; Zhang, Zuxin

    2012-01-01

    The yield of maize grain is a highly complex quantitative trait that is controlled by multiple quantitative trait loci (QTLs) with small effects, and is frequently influenced by multiple genetic and environmental factors. Thus, it is challenging to clone a QTL for grain yield in the maize genome. Previously, we identified a major QTL, qKNPR6, for kernel number per row (KNPR) across multiple environments, and developed two nearly isogenic lines, SL57-6 and Ye478, which differ only in the allelic constitution at the short segment harboring the QTL. Recently, qKNPR6 was re-evaluated in segregating populations derived from SL57-6×Ye478, and was narrowed down to a 2.8 cM interval, which explained 56.3% of the phenotypic variance of KNPR in 201 F(2∶3) families. The QTL simultaneously affected ear length, kernel weight and grain yield. Furthermore, a large F(2) population with more than 12,800 plants, 191 recombinant chromosomes and 10 overlapping recombinant lines placed qKNPR6 into a 0.91 cM interval corresponding to 198Kb of the B73 reference genome. In this region, six genes with expressed sequence tag (EST) evidence were annotated. The expression pattern and DNA diversity of the six genes were assayed in Ye478 and SL57-6. The possible candidate gene and the pathway involved in inflorescence development were discussed.

  19. Pleiotropic genetic effects influencing sleep and neurological disorders.

    PubMed

    Veatch, Olivia J; Keenan, Brendan T; Gehrman, Philip R; Malow, Beth A; Pack, Allan I

    2017-02-01

    Research evidence increasingly points to the large impact of sleep disturbances on public health. Many aspects of sleep are heritable and genes influencing traits such as timing, EEG characteristics, sleep duration, and response to sleep loss have been identified. Notably, large-scale genome-wide analyses have implicated numerous genes with small effects on sleep timing. Additionally, there has been considerable progress in the identification of genes influencing risk for some neurological sleep disorders. For restless legs syndrome, implicated variants are typically in genes associated with neuronal development. By contrast, genes conferring risk for narcolepsy function in the immune system. Many genetic variants associated with sleep disorders are also implicated in neurological disorders in which sleep abnormalities are common; for example, variation in genes involved in synaptic homoeostasis are implicated in autism spectrum disorder and sleep-wake control. Further investigation into pleiotropic roles of genes influencing both sleep and neurological disorders could lead to new treatment strategies for a variety of sleep disturbances. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Pleiotropic Effects of Statins on the Cardiovascular System.

    PubMed

    Oesterle, Adam; Laufs, Ulrich; Liao, James K

    2017-01-06

    The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease. © 2017 American Heart Association, Inc.

  1. Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms*

    PubMed Central

    Grimm, Marcus O. W.; Kuchenbecker, Johanna; Grösgen, Sven; Burg, Verena K.; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Friess, Petra; de Wilde, Martijn C.; Broersen, Laus M.; Penke, Botond; Péter, Mária; Vígh, László; Grimm, Heike S.; Hartmann, Tobias

    2011-01-01

    Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID:21324907

  2. Pleiotropic functions of EAPII/TTRAP/TDP2

    PubMed Central

    Li, Chunyang; Sun, Shi-Yong; Khuri, Fadlo R

    2011-01-01

    EAPII (also called TTRAP, TDP2), a protein identified a decade ago, has recently been shown to function as an oncogenic factor. This protein was also proven to be the first 5′-tyrosyl-DNA phosphodiesterase. EAPII has been demonstrated to have promiscuous protein associations, broad responsiveness to various extracellular signals and pleiotropic functions in the development of human diseases including cancer and neurodegenerative disease. Emerging data suggest that EAPII is a multi-functional protein: EAPII repairs enzyme (topoisomerase)-mediated DNA damage by removing phosphotyrosine from DNA adducts; EAPII is involved in multiple signal transduction pathways such as TNF-TNFR, TGF? and MAPK, and EAPII is responsive to immune defense, inflammatory response, virus infection and DNA toxins (chemo or radiation therapy). This review focuses on the current understanding of EAPII biology and its potential relations to many aspects of cancer development, including chromosome instability, tumorigenesis, tumor metastasis and chemoresistance, suggesting it as a potential target for intervention in cancer and other human diseases. PMID:21926483

  3. Genetics of the Musculoskeletal System: A Pleiotropic Approach

    PubMed Central

    Karasik, David; Kiel, Douglas P

    2012-01-01

    The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment. PMID:18269309

  4. Pleiotropic roles of cold shock domain proteins in plants.

    PubMed

    Sasaki, Kentaro; Imai, Ryozo

    2011-01-01

    The cold shock domain (CSD) is a nucleic acid binding domain that is widely conserved from bacteria to higher plants and animals. In Escherichia coli, cold shock proteins (CSPs) are composed solely of a CSD and function as RNA chaperones that destabilize RNA secondary structures. Cellular RNAs tend to be folded into unfavorable structures under low temperature conditions, and RNA chaperones resolve these structures, recovering functionality of the RNAs. CSP functions are associated mainly with cold adaptation, but they are also involved in other biological processes under normal growth conditions. Eukaryotic CSD proteins contain auxiliary domains in addition to the CSD and regulate many biological processes such as development and stress tolerance. In plants, it has been demonstrated that CSD proteins play essential roles in acquiring freezing tolerance. In addition, it has been suggested that some plant CSD proteins regulate embryo development, flowering time, and fruit development. In this review, we summarize the pleiotropic biological functions of CSP proteins in plants and discuss possible mechanisms by which plant CSD proteins regulate the functions of RNA molecules.

  5. IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology

    PubMed Central

    Croce, Michela; Rigo, Valentina; Ferrini, Silvano

    2015-01-01

    Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21's antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy. PMID:25961061

  6. A natural variant of NAL1, selected in high-yield rice breeding programs, pleiotropically increases photosynthesis rate

    PubMed Central

    Takai, Toshiyuki; Adachi, Shunsuke; Taguchi-Shiobara, Fumio; Sanoh-Arai, Yumiko; Iwasawa, Norio; Yoshinaga, Satoshi; Hirose, Sakiko; Taniguchi, Yojiro; Yamanouchi, Utako; Wu, Jianzhong; Matsumoto, Takashi; Sugimoto, Kazuhiko; Kondo, Katsuhiko; Ikka, Takashi; Ando, Tsuyu; Kono, Izumi; Ito, Sachie; Shomura, Ayahiko; Ookawa, Taiichiro; Hirasawa, Tadashi; Yano, Masahiro; Kondo, Motohiko; Yamamoto, Toshio

    2013-01-01

    Improvement of leaf photosynthesis is an important strategy for greater crop productivity. Here we show that the quantitative trait locus GPS (GREEN FOR PHOTOSYNTHESIS) in rice (Oryza sativa L.) controls photosynthesis rate by regulating carboxylation efficiency. Map-based cloning revealed that GPS is identical to NAL1 (NARROW LEAF1), a gene previously reported to control lateral leaf growth. The high-photosynthesis allele of GPS was found to be a partial loss-of-function allele of NAL1. This allele increased mesophyll cell number between vascular bundles, which led to thickened leaves, and it pleiotropically enhanced photosynthesis rate without the detrimental side effects observed in previously identified nal1 mutants, such as dwarf plant stature. Furthermore, pedigree analysis suggested that rice breeders have repeatedly selected the high-photosynthesis allele in high-yield breeding programs. The identification and utilization of NAL1 (GPS) can enhance future high-yield breeding and provides a new strategy for increasing rice productivity. PMID:23985993

  7. Lack of a type-2 glycosyltransferase in the fish pathogen Flavobacterium psychrophilum determines pleiotropic changes and loss of virulence.

    PubMed

    Pérez-Pascual, David; Gómez, Esther; Guijarro, José A

    2015-01-13

    Flavobacterium psychrophilum is an important fish pathogen, responsible for Cold Water Disease, with a significant economic impact on salmonid farms worldwide. In spite of this, little is known about the bacterial physiology and pathogenesis mechanisms, maybe because it is difficult to manipulate, being considered a fastidious microorganism. Mutants obtained using a Tn4351 transposon were screened in order to identify those with alteration in colony morphology, colony spreading and extracellular proteolytic activity, amongst other phenotypes. A F. psychrophilum mutant lacking gliding motility showed interruption of the FP1638 locus that encodes a putative type-2 glycosyltransferase (from here on referred to as fpgA gene, Flavobacterium psychrophilum glycosyltransferase). Additionally, the mutant also showed a decrease in the extracellular proteolytic activity as a consequence of down regulation in the fpgA mutant background of the fpp2-fpp1 operon promoter, responsible for the major extracellular proteolytic activity of the bacterium. The protein glycosylation profile of the parental strain showed the presence of a 22 kDa glycosylated protein which is lost in the mutant. Complementation with the fpgA gene led to the recovery of the wild-type phenotype. LD50 experiments in the rainbow trout infection model show that the mutant was highly attenuated. The pleiotropic phenotype of the mutant demonstrated the importance of this glycosyltranferase in the physiology and virulence of the bacterium. Moreover, the fpgA mutant strain could be considered a good candidate for the design of an attenuated vaccine.

  8. Pleiotropic, heart rate-independent cardioprotection by ivabradine

    PubMed Central

    Kleinbongard, P; Gedik, N; Witting, P; Freedman, B; Klöcker, N; Heusch, G

    2015-01-01

    Background and Purpose In pigs, ivabradine reduces infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of this non-heart rate-related cardioprotection is unknown. Hence, in the present study we assessed the pleiotropic action of ivabradine in more detail. Experimental Approach Anaesthetized mice were pretreated with ivabradine (1.7 mg·kg−1 i.v.) or placebo (control) before a cycle of coronary occlusion/reperfusion (30/120 min ± left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) in the absence and presence of ivabradine, viability was then quantified and intra- and extracellular reactive oxygen species (ROS) formation was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and ADP-containing buffer in the absence and presence of ivabradine respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial ATP production and calcium retention capacity (CRC) were assessed. Key Results Ivabradine decreased infarct size even with atrial pacing. Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradin, the accumulation of intra- and extracellular ROS decreased in parallel. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS, increased mitochondrial ATP production and increased CRC. Conclusion and Implications Ivabradine reduces infarct size independently of a reduction in heart rate and improves ventricular cardiomyocyte viability, possibly by reducing mitochondrial ROS formation, increasing ATP production and CRC. PMID:26076181

  9. Pleiotropic, heart rate-independent cardioprotection by ivabradine.

    PubMed

    Kleinbongard, P; Gedik, N; Witting, P; Freedman, B; Klöcker, N; Heusch, G

    2015-09-01

    In pigs, ivabradine reduces infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of this non-heart rate-related cardioprotection is unknown. Hence, in the present study we assessed the pleiotropic action of ivabradine in more detail. Anaesthetized mice were pretreated with ivabradine (1.7 mg · kg(-1) i.v.) or placebo (control) before a cycle of coronary occlusion/reperfusion (30/120 min ± left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) in the absence and presence of ivabradine, viability was then quantified and intra- and extracellular reactive oxygen species (ROS) formation was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and ADP-containing buffer in the absence and presence of ivabradine respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial ATP production and calcium retention capacity (CRC) were assessed. Ivabradine decreased infarct size even with atrial pacing. Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradine, the accumulation of intra- and extracellular ROS decreased in parallel. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS, increased mitochondrial ATP production and increased CRC. Ivabradine reduces infarct size independently of a reduction in heart rate and improves ventricular cardiomyocyte viability, possibly by reducing mitochondrial ROS formation, increasing ATP production and CRC. © 2015 The British Pharmacological Society.

  10. Pleiotropic contributions of nitric oxide to aggressive behavior.

    PubMed

    Nelson, Randy J; Trainor, Brian C; Chiavegatto, Silvana; Demas, Gregory E

    2006-01-01

    Male mice with targeted deletion of the genes encoding the neuronal (NOS-1-/- or nNOS-/-) isoform of nitric oxide synthase display altered aggressive behaviors. Male nNOS-1-/- mice are more aggressive than wild-type (WT) mice in all testing paradigms. Testosterone is necessary, but not sufficient, for evoking the persistent aggression, and that serotonin (5-HT) metabolism is altered in male nNOS-1-/- mice. The specific deletion of the nNOS-1 gene not only results in a lack of nNOS-1 protein, but in common with many genes, affects several 'down-stream' processes. In this review, we address whether the elevated aggression in male nNOS-1-/- mice reflects pleiotropic effects of the nNOS-1 gene on pain sensitivity, 'anxiety-like', or 'depressive-like' behaviors. For example, male nNOS-1-/- mice display increased sensitivity to painful stimuli, which may prolong aggressive interactions. Despite elevated corticosterone concentrations, nNOS-1 knockout mice appear to be less 'anxious' or fearful than WT mice. Male nNOS-1-/- mice display longer latencies to right themselves on an inverted platform and spend more time in the center of an open field than WT mice. Because of reduced serotonin turnover, the excessive aggressiveness displayed by nNOS-1-/- mice may be symptomatic of a depressive-like syndrome. However, nNOS-1-/- mice rarely display behavioral 'despair' when assessed with the Porsolt forced swim test; rather, nNOS-1-/- mice show vigorous swimming throughout the assessment suggesting that the aggressive behavior does not represent depressive-like behavior. Importantly, aggressive behavior is not a unitary process, but is the result of complex interactions among several physiological, motivational, and behavioral systems, with contributions from the social as well as the physical environment. Lastly, the multiple, and often unanticipated, effects of targeted gene disruption on aggressive behavior are considered.

  11. Pleiotropic mechanisms facilitated by resveratrol and its metabolites

    PubMed Central

    CALAMINI, Barbara; RATIA, Kiira; MALKOWSKI, Michael G.; CUENDET, Muriel; PEZZUTO, John M.; SANTARSIERO, Bernard D.; MESECAR, Andrew D.

    2011-01-01

    Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4′-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4′-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself. PMID:20450491

  12. Pleiotropic mechanisms facilitated by resveratrol and its metabolites

    SciTech Connect

    Calamini, Barbara; Ratia, Kiira; Malkowski, Michael G.; Cuendet, Muriel; Pezzuto, John M.; Santarsiero, Bernard D.; Mesecar, Andrew D.

    2010-07-01

    Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD{sup +}-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4{prime}-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4?-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.

  13. Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution.

    PubMed

    Utrilla, Jose; O'Brien, Edward J; Chen, Ke; McCloskey, Douglas; Cheung, Jacky; Wang, Harris; Armenta-Medina, Dagoberto; Feist, Adam M; Palsson, Bernhard O

    2016-04-27

    Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear selection pressures. Here, several ALE-selected single-mutation variants in RNA polymerase (RNAP) of Escherichia coli are detailed using an integrated multi-scale experimental and computational approach. While these mutations increase cellular growth rates in steady environments, they reduce tolerance to stress and environmental fluctuations. We detail structural changes in the RNAP that rewire the transcriptional machinery to rebalance proteome and energy allocation toward growth and away from several hedging and stress functions. We find that while these mutations occur in diverse locations in the RNAP, they share a common adaptive mechanism. In turn, these findings highlight the resource allocation trade-offs organisms face and suggest how the structure of the regulatory network enhances evolvability. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. History of the discovery of a master locus producing piRNAs: the flamenco/COM locus in Drosophila melanogaster

    PubMed Central

    Coline, Goriaux; Théron, Emmanuelle; Brasset, Emilie; Vaury, Chantal

    2014-01-01

    The discovery of transposable elements (TEs) in the 1950s by B. McClintock implied the existence of cellular regulatory systems controlling TE activity. The discovery of flamenco (flam) an heterochromatic locus from Drosophila melanogaster and its ability to survey several TEs such as gypsy, ZAM, and Idefix contributed to peer deeply into the mechanisms of the genetic and epigenetic regulation of TEs. flam was the first cluster producing small RNAs to be discovered long before RNAi pathways were identified in 1998. As a result of the detailed genetic analyses performed by certain laboratories and of the sophisticated genetic tools they developed, this locus has played a major role in our understanding of piRNA mediated TE repression in animals. Here we review the first discovery of this locus and retrace decades of studies that led to our current understanding of the relationship between genomes and their TE targets. PMID:25136352

  15. History of the discovery of a master locus producing piRNAs: the flamenco/COM locus in Drosophila melanogaster.

    PubMed

    Goriaux, Coline; Théron, Emmanuelle; Brasset, Emilie; Vaury, Chantal

    2014-01-01

    The discovery of transposable elements (TEs) in the 1950s by B. McClintock implied the existence of cellular regulatory systems controlling TE activity. The discovery of flamenco (flam) an heterochromatic locus from Drosophila melanogaster and its ability to survey several TEs such as gypsy, ZAM, and Idefix contributed to peer deeply into the mechanisms of the genetic and epigenetic regulation of TEs. flam was the first cluster producing small RNAs to be discovered long before RNAi pathways were identified in 1998. As a result of the detailed genetic analyses performed by certain laboratories and of the sophisticated genetic tools they developed, this locus has played a major role in our understanding of piRNA mediated TE repression in animals. Here we review the first discovery of this locus and retrace decades of studies that led to our current understanding of the relationship between genomes and their TE targets.

  16. The Molecular Revolution in Cutaneous Biology: EDC and Locus Control.

    PubMed

    Oh, Inez Y; de Guzman Strong, Cristina

    2017-05-01

    The epidermal differentiation complex (EDC) locus consists of a cluster of genes important for the terminal differentiation of the epidermis. While early studies identified the functional importance of individual EDC genes, the recognition of the EDC genes as a cluster with its shared biology, homology, and physical linkage was pivotal to later studies that investigated the transcriptional regulation of the locus. Evolutionary conservation of the EDC and the transcriptional activation during epidermal differentiation suggested a cis-regulatory mechanism via conserved noncoding elements or enhancers. This line of pursuit led to the identification of CNE 923, an epidermal-specific enhancer that was found to mediate chromatin remodeling of the EDC in an AP-1 dependent manner. These genomic studies, as well as the advent of high-throughput sequencing and genome engineering techniques, have paved the way for future investigation into enhancer-mediated regulatory networks in cutaneous biology. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Evolutionary rewiring of bacterial regulatory networks

    PubMed Central

    Taylor, Tiffany B.; Mulley, Geraldine; McGuffin, Liam J.; Johnson, Louise J.; Brockhurst, Michael A.; Arseneault, Tanya; Silby, Mark W.; Jackson, Robert W.

    2015-01-01

    Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks - homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor, et al. Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs. PMID:28357301

  18. Bifurcations of the conjugate locus

    NASA Astrophysics Data System (ADS)

    Waters, Thomas

    2017-09-01

    The conjugate locus of a point p in a surface S will have a certain number of cusps. As the point p is moved in the surface the conjugate locus may spontaneously gain or lose cusps. In this paper we explain this 'bifurcation' in terms of the vanishing of higher derivatives of the exponential map; we derive simple equations for these higher derivatives in terms of scalar invariants; we classify the bifurcations of cusps in terms of the local structure of the conjugate locus; and we describe an intuitive picture of the bifurcation as the intersection between certain contours in the tangent plane.

  19. Genetic analysis of a pleiotropic deletion mutation (delta igf) in Bacillus subtilis.

    PubMed Central

    Fujita, Y; Fujita, T

    1983-01-01

    A delta igf mutation of Bacillus subtilis (formerly called fdpAl) is a large deletion causing pleiotropic defects. The mapping of the delta igf deletion by phage PBS1 transduction revealed the following map order: sacA, thiC, hsrE, delta igf, ts199, purA. To analyze the pleiotropic nature of the delta igf mutation, mutants affected in each property of the pleiotropic mutation were isolated, and the mutations were mapped. iol and gnt mutants could not grow on inositol and gluconate, respectively, and fdp mutants were affected only in fructose-bisphosphatase. The map order from sacA to purA was as follows: sacA, thiC, hsrE, iol-6, gnt-4, fdp-74, hsrB, ts199, purA. The delta igf deletion covered loci from iol-6 to hsrB. PMID:6302085

  20. PAPA: a flexible tool for identifying pleiotropic pathways using genome-wide association study summaries.

    PubMed

    Wen, Yan; Wang, Wenyu; Guo, Xiong; Zhang, Feng

    2016-03-15

    : Pleiotropy is common in the genetic architectures of complex diseases. To the best of our knowledge, no analysis tool has been developed for identifying pleiotropic pathways using multiple genome-wide association study (GWAS) summaries by now. Here, we present PAPA, a flexible tool for pleiotropic pathway analysis utilizing GWAS summary results. The performance of PAPA was validated using publicly available GWAS summaries of body mass index and waist-hip ratio of the GIANT datasets. PAPA identified a set of pleiotropic pathways, which have been demonstrated to be involved in the development of obesity. PAPA program, document and illustrative example are available at http://sourceforge.net/projects/papav1/files/ : fzhxjtu@mail.xjtu.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Pleiotropic Effects of Antiarrhythmic Agents: Dronedarone in the Treatment of Atrial Fibrillation

    PubMed Central

    Heijman, Jordi; Heusch, Gerd; Dobrev, Dobromir

    2013-01-01

    Atrial fibrillation remains the most common arrhythmia in clinical practice. Dronedarone is an antiarrhythmic drug for the maintenance of sinus rhythm in patients with atrial fibrillation. Dronedarone is an amiodarone derivative developed to reduce the number of extracardiovascular side effects. Dronedarone has undergone extensive experimental and clinical testing during the last decade. On the aggregate, these studies have highlighted a complex set of pleiotropic actions that may contribute to dronedarone’s antiarrhythmic effects. In this review, we summarize the clinical studies that have evaluated dronedarone and provide an overview of dronedarone’s electrophysiological and nonelectrophysiological pleiotropic actions. PMID:23997577

  2. Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO, and CCFR Consortia

    PubMed Central

    Cheng, Iona; Kocarnik, Jonathan M; Dumitrescu, Logan; Lindor, Noralane M; Chang-Claude, Jenny; Avery, Christy L.; Caberto, Christian P; Love, Shelly-Ann; Slattery, Martha L; Chan, Andrew T; Baron, John A; Hindorff, Lucia A; Park, Sungshim Lani; Schumacher, Fredrick R; Hoffmeister, Michael; Kraft, Peter; Butler, Anne; Duggan, David; Hou, Lifang; Carlson, Chris S; Monroe, Kristine R; Lin, Yi; Carty, Cara L; Mann, Sue; Ma, Jing; Giovannucci, Edward L; Fuchs, Charles S; Newcomb, Polly A; Jenkins, Mark A; Hopper, John L; Haile, Robert W; Conti, David V; Campbell, Peter T; Potter, John D; Caan, Bette J; Schoen, Robert E; Hayes, Richard B; Chanock, Stephen J; Berndt, Sonja I; Kury, Sebastien; Bezieau, Stephane; Ambite, Jose Luis; Kumaraguruparan, Gowri; Richardson, Danielle; Goodloe, Robert J; Dilks, Holli H; Baker, Paxton; Zanke, Brent W; Lemire, Mathieu; Gallinger, Steven; Hsu, Li; Jiao, Shuo; Harrison, Tabitha; Seminara, Daniela; Haiman, Christopher A; Kooperberg, Charles; Wilkens, Lynne R; Hutter, Carolyn M; White, Emily; Crawford, Dana C; Heiss, Gerardo; Hudson, Thomas J; Brenner, Hermann; Bush, William S; Casey, Graham; Marchand, Loic Le; Peters, Ulrike

    2013-01-01

    Objective Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13,338 colorectal cancer cases and 40,967 controls from three consortia: Population Architecture using Genetics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p-value of 2.92×10−4 was used to determine statistical significance of the associations. Results Two correlated SNPs— rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI: 1.07–1.18; P=1.74×10−5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusion This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer, thus adding colorectal cancer to the list of cancer sites linked to this particular multi-cancer risk region at 8q24. PMID:23935004

  3. Rab32 subfamily small GTPases: pleiotropic Rabs in endosomal trafficking.

    PubMed

    Ohbayashi, Norihiko; Fukuda, Mitsunori; Kanaho, Yasunori

    2017-08-01

    Rab small GTPases, well-known regulators of membrane trafficking pathways in eukaryotic cells, comprise approximately 60 different members in mammals. During the past decade, our understanding of the functions of mammalian Rab32 subfamily members (Rab32 and Rab38) have deepened, especially on the biogenesis of lysosome-related organelles, such as melanosomes, and the protection mechanisms against several pathogenic microbial infections. Endosome-mediated membrane trafficking by Rab32 subfamily members plays pivotal roles in these events. In this review, we provide an overview of the regulatory mechanisms of mammalian Rab32-family members in endosomal trafficking, especially focusing on their GEF, GAP and effector molecules, and describe the latest findings on physiological and pathological functions regulated by these molecules. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  4. Pleiotropic functions of the yeast Greatwall-family protein kinase Rim15p: a novel target for the control of alcoholic fermentation.

    PubMed

    Watanabe, Daisuke; Takagi, Hiroshi

    2017-06-01

    Rim15p, a Greatwall-family protein kinase in yeast Saccharomyces cerevisiae, is required for cellular nutrient responses, such as the entry into quiescence and the induction of meiosis and sporulation. In higher eukaryotes, the orthologous gene products are commonly involved in the cell cycle G2/M transition. How are these pleiotropic functions generated from a single family of protein kinases? Recent advances in both research fields have identified the conserved Greatwall-mediated signaling pathway and a variety of downstream target molecules. In addition, our studies of S. cerevisiae sake yeast strains revealed that Rim15p also plays a significant role in the control of alcoholic fermentation. Despite an extensive history of research on glycolysis and alcoholic fermentation, there has been no critical clue to artificial modification of fermentation performance of yeast cells. Our finding of an in vivo metabolic regulatory mechanism is expected to provide a major breakthrough in yeast breeding technologies for fermentation applications.

  5. The SCL gene is formed from a transcriptionally complex locus.

    PubMed Central

    Aplan, P D; Begley, C G; Bertness, V; Nussmeier, M; Ezquerra, A; Coligan, J; Kirsch, I R

    1990-01-01

    We describe the structural organization of the human SCL gene, a helix-loop-helix family member which we believe plays a fundamental role in hematopoietic differentiation. The SCL locus is composed of eight exons distributed over 16 kb. SCL shows a pattern of expression quite restricted to early hematopoietic tissues, although in malignant states expression of the gene may be somewhat extended into later developmental stages. A detailed analysis of the transcript(s) arising from the SCL locus revealed that (i) the 5' noncoding portion of the SCL transcript, which resides within a CpG island, has a complex pattern of alternative exon utilization as well as two distinct transcription initiation sites; (ii) the 5' portions of the SCL transcript contain features that suggest a possible regulatory role for these segments; (iii) the pattern of utilization of the 5' exons is cell lineage dependent; and (iv) all of the currently studied chromosomal aberrations that affect the SCL locus either structurally or functionally eliminate the normal 5' transcription initiation sites. These data suggest that the SCL gene, and specifically its 5' region, may be a target for regulatory interactions during early hematopoietic development. Images PMID:2247063

  6. Molecular Epidemiology of sil Locus in Clinical Streptococcus pyogenes Strains

    PubMed Central

    Plainvert, Céline; Dinis, Márcia; Ravins, Miriam; Hanski, Emanuel; Touak, Gérald; Dmytruk, Nicolas; Fouet, Agnès

    2014-01-01

    Streptococcus pyogenes (group A Streptococcus [GAS]) causes a wide variety of diseases, ranging from mild noninvasive to severe invasive infections. Mutations in regulatory components have been implicated in the switch from colonization to invasive phenotypes. The inactivation of the sil locus, composed of six genes encoding a quorum-sensing complex, gives rise to a highly invasive strain. However, studies conducted on limited collections of GAS strains suggested that sil prevalence is around 15%; furthermore, whereas a correlation between the presence of sil and the genetic background was suggested, no link between the presence of a functional sil locus and the invasive status was assessed. We established a collection of 637 nonredundant strains covering all emm genotypes present in France and of known clinical history; 68%, 22%, and 10% were from invasive infections, noninvasive infections, and asymptomatic carriage, respectively. Among the 637 strains, 206 were sil positive. The prevalence of the sil locus varied according to the emm genotype, being present in >85% of the emm4, emm18, emm32, emm60, emm87, and emm90 strains and absent from all emm1, emm28, and emm89 strains. A random selection based on 2009 French epidemiological data indicated that 16% of GAS strains are sil positive. Moreover, due to mutations leading to truncated proteins, only 9% of GAS strains harbor a predicted functional sil system. No correlation was observed between the presence or absence of a functional sil locus and the strain invasiveness status. PMID:24671796

  7. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

    PubMed Central

    Christakos, Sylvia; Dhawan, Puneet; Verstuyf, Annemieke; Verlinden, Lieve; Carmeliet, Geert

    2016-01-01

    1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease. PMID:26681795

  8. A quantitative trait locus influencing anxiety in the laboratory rat.

    PubMed

    Fernández-Teruel, Alberto; Escorihuela, Rosa M; Gray, Jeffrey A; Aguilar, Raúl; Gil, Luis; Giménez-Llort, Lydia; Tobeña, Adolf; Bhomra, Amarjit; Nicod, Alison; Mott, Richard; Driscoll, Peter; Dawson, Gerard R; Flint, Jonathan

    2002-04-01

    A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans.

  9. A Quantitative Trait Locus Influencing Anxiety in the Laboratory Rat

    PubMed Central

    Fernández-Teruel, Alberto; Escorihuela, Rosa M.; Gray, Jeffrey A.; Aguilar, Raúl; Gil, Luis; Giménez-Llort, Lydia; Tobeña, Adolf; Bhomra, Amarjit; Nicod, Alison; Mott, Richard; Driscoll, Peter; Dawson, Gerard R.; Flint, Jonathan

    2002-01-01

    A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans. PMID:11932246

  10. [Study on preferred retinal locus].

    PubMed

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  11. Locus of Control and Delinquency.

    ERIC Educational Resources Information Center

    Parrott, C. A.; Strongman, K. T.

    1984-01-01

    Assessed delinquent and nondelinquent male adolescents (N=43) on locus of control and intellectual achievement responsibilty. Results supported a multidimensional model. There was no difference in expectancy of control for negative academic events between delinquents and nondelinquents. Birth order and delinquency were the most important…

  12. Locus of Control and Socialization.

    ERIC Educational Resources Information Center

    Raine, Adrian; And Others

    1982-01-01

    Predicted that an external locus of control would characterize undersocialization. Tested this hypothesis on a random sample of secondary school children (N=97). Scores from the Child Nowicki-Strickland Internal-External Scale were found to predict undersocialization in the expected direction. Suggested several possible interpretations of this…

  13. Locus of Control and Interpersonal Attraction.

    ERIC Educational Resources Information Center

    Fagan, M. Michael

    1980-01-01

    The role of locus of control in interpersonal attraction was examined by administering 1) the Nowicki-Strickland Locus of Control Scale and 2) a sociometric test of friendship to 200 eighth graders. (CM)

  14. Pleiotropic effects of cardiac drugs on healing post-MI. The good, bad, and ugly.

    PubMed

    Jugdutt, Bodh I

    2008-12-01

    Healing after myocardial infarction (MI) is a well-orchestrated time-dependent process that involves inflammation, tissue repair with extracellular collagen matrix (ECCM) deposition and scar formation, and remodeling of myocardial structure, matrix, vasculature, and function. Rapid early ECCM degradation followed by slow ECCM replacement and maturation during post-MI healing results in a prolonged window of enhanced vulnerability to adverse remodeling. Decreased ECCM results in adverse ventricular remodeling, dysfunction, and rupture. Inflammation, a critical factor in normal healing, if impaired results in adverse remodeling and rupture. Several therapeutic drugs prescribed after MI exert pleiotropic effects that suppress ECCM and inflammation during healing and may have good, bad, or ugly consequences. This article reviews the potential impact of pleiotropic effects of some prototypic cardiac drugs such as renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, and thrombolytics during healing post-ST-segment-elevation MI (STEMI), with special focus on inflammation, ECCM and remodeling, and implications in the elderly.

  15. Exploitation of pleiotropic actions of statins by using tumour-targeted delivery systems.

    PubMed

    Licarete, Emilia; Sesarman, Alina; Banciu, Manuela

    2015-01-01

    Statins are drugs traditionally used to lower cholesterol levels in blood. At concentrations 100- to 500-fold higher than those needed for reaching cholesterol lowering activity, they have anti-tumour activity. This anti-tumour activity is based on statins pleiotropic effects derived from their ability to inhibit the mevalonate synthesis and include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-inflammatory, anti-metastatic actions and modulatory effects on intra-tumour oxidative stress. Thus, in this review, we summarise the possible pleiotropic actions of statins involved in tumour growth inhibition. Since the administration of these high doses of statins is accompanied by severe side effects, targeted delivery of statins seems to be the appropriate strategy for efficient application of statins in oncology. Therefore, we also present an overview of the current status of targeted delivery systems for statins with possible utilisation in oncology.

  16. Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer.

    PubMed

    Peng, Cheng; Lou, Hui-Ling; Liu, Feng; Shen, Jie; Lin, Xu; Zeng, Chun-Ping; Long, Ji-Rong; Su, Kuan-Jui; Zhang, Lan; Greenbaum, Jonathan; Deng, Wei-Feng; Li, Yu-Mei; Deng, Hong-Wen

    2017-07-31

    Epidemiological and clinical evidences have shown that bone mineral density (BMD) has a close relationship with breast cancer (BC). They might potentially have a shared genetic basis. By incorporating information about these pleiotropic effects, we may be able to explore more of the traits' total heritability. We applied a recently developed conditional false discovery rate (cFDR) method to the summary statistics from two independent GWASs to identify the potential pleiotropic genetic variants for BMD and BC. By jointly analyzing two large independent GWASs of BMD and BC, we found strong pleiotropic enrichment between them and identified 102 single-nucleotide polymorphisms (SNPs) in BMD and 192 SNPs in BC with cFDR < 0.05, including 230 SNPs that might have been overlooked by the standard GWAS analysis. cFDR-significant genes were enriched in GO terms and KEGG pathways which were crucial to bone metabolism and/or BC pathology (adjP < 0.05). Some cFDR-significant genes were partially validated in the gene expressional validation assay. Strong interactions were found between proteins produced by cFDR-significant genes in the context of biological mechanism of bone metabolism and/or BC etiology. Totally, we identified 7 pleiotropic SNPs that were associated with both BMD and BC (conjunction cFDR < 0.05); CCDC170, ESR1, RANKL, CPED1, and MEOX1 might play important roles in the pleiotropy of BMD and BC. Our study highlighted the significant pleiotropy between BMD and BC and shed novel insight into trait-specific as well as the potentially shared genetic architecture for both BMD and BC.

  17. Locus of Control and Status Attainment.

    ERIC Educational Resources Information Center

    Bensman, Miriam Roza; Haller, Archibald O.

    Utilizing data derived from 277 rural, male respondents initially enrolled in Lenawee County, Michigan high schools, the Rotter's Internal-External Locus of Control Scale was employed to test the hypothesis that locus of control will have interactive rather than additive effects on the process of status attainment. Locus of control was defined as…

  18. Pleiotropic effects of coat colour-associated mutations in humans, mice and other mammals.

    PubMed

    Reissmann, Monika; Ludwig, Arne

    2013-01-01

    The characterisation of the pleiotropic effects of coat colour-associated mutations in mammals illustrates that sensory organs and nerves are particularly affected by disorders because of the shared origin of melanocytes and neurocytes in the neural crest; e.g. the eye-colour is a valuable indicator of disorders in pigment production and eye dysfunctions. Disorders related to coat colour-associated alleles also occur in the skin (melanoma), reproductive tract and immune system. Additionally, the coat colour phenotype of an individual influences its general behaviour and fitness. Mutations in the same genes often produce similar coat colours and pleiotropic effects in different species (e.g., KIT [reproductive disorders, lethality], EDNRB [megacolon] and LYST [CHS]). Whereas similar disorders and similar-looking coat colour phenotypes sometimes have a different genetic background (e.g., deafness [EDN3/EDNRB, MITF, PAX and SNAI2] and visual diseases [OCA2, RAB38, SLC24A5, SLC45A2, TRPM1 and TYR]). The human predilection for fancy phenotypes that ignore disorders and genetic defects is a major driving force for the increase of pleiotropic effects in domestic species and laboratory subjects since domestication has commenced approximately 18,000 years ago. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Assessment of pleiotropic transcriptome perturbations in Arabidopsis engineered for indirect insect defence

    PubMed Central

    2014-01-01

    Background Molecular characterization is an essential step of risk/safety assessment of genetically modified (GM) crops. Holistic approaches for molecular characterization using omics platforms can be used to confirm the intended impact of the genetic engineering, but can also reveal the unintended changes at the omics level as a first assessment of potential risks. The potential of omics platforms for risk assessment of GM crops has rarely been used for this purpose because of the lack of a consensus reference and statistical methods to judge the significance or importance of the pleiotropic changes in GM plants. Here we propose a meta data analysis approach to the analysis of GM plants, by measuring the transcriptome distance to untransformed wild-types. Results In the statistical analysis of the transcriptome distance between GM and wild-type plants, values are compared with naturally occurring transcriptome distances in non-GM counterparts obtained from a database. Using this approach we show that the pleiotropic effect of genes involved in indirect insect defence traits is substantially equivalent to the variation in gene expression occurring naturally in Arabidopsis. Conclusion Transcriptome distance is a useful screening method to obtain insight in the pleiotropic effects of genetic modification. PMID:24947327

  20. Pleiotropic effects of hemagglutinin amino acid substitutions of H5 influenza escape mutants

    SciTech Connect

    Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.; Krylov, Petr S.; Ilyushina, Natalia A.; Kaverin, Nikolai V.

    2013-12-15

    In the present study we assessed pleiotropic characteristics of the antibody-selected mutations. We examined pH optimum of fusion, temperatures of HA heat inactivation, and in vitro and in vivo replication kinetics of the previously obtained influenza H5 escape mutants. Our results showed that HA1 N142K mutation significantly lowered the pH of fusion optimum. Mutations of the escape mutants located in the HA lateral loop significantly affected H5 HA thermostability (P<0.05). HA changes at positions 131, 144, 145, and 156 and substitutions at positions 131, 142, 145, and 156 affected the replicative ability of H5 escape mutants in vitro and in vivo, respectively. Overall, a co-variation between antigenic specificity and different HA phenotypic properties has been demonstrated. We believe that the monitoring of pleiotropic effects of the HA mutations found in H5 escape mutants is essential for accurate prediction of mutants with pandemic potential. - Highlights: • HA1 N142K mutation significantly lowered the pH of fusion optimum. • Mutations located in the HA lateral loop significantly affected H5 HA thermostability. • HA changes at positions 131, 142, 144, 145, and 156 affected the replicative ability of H5 mutants. • Acquisition of glycosylation site could lead to the emergence of multiple pleiotropic effects.

  1. Pleiotropic and Adverse Effects of Statins-Do Epigenetics Play a Role?

    PubMed

    Allen, Stephanie C; Mamotte, Cyril D S

    2017-08-01

    Statins are widely used to prevent major cardiovascular events by lowering serum cholesterol. There is evidence that statins have pleiotropic effects-that is, cholesterol-independent effects-that may also confer protection from cardiovascular disease and potentially numerous other pathologies, including cancer. Statins also have a number of well described adverse effects, including myopathy, rhabdomyolysis, liver damage, and type 2 diabetes. This paper examines the evidence of epigenetic modifications as a contributory factor to the pleiotropic and adverse effects of statins. In vitro and animal studies have shown that statins can inhibit histone deacetylase activity and increase histone acetylation. Similarly, there is evidence that statins may inhibit both histone and DNA methyltransferases and subsequently demethylate histone residues and DNA, respectively. These changes have been shown to alter expression of various genes, including tumor suppressor genes and genes thought to have anti-atherosclerotic actions. Statins have also been shown to influence the expression of numerous microRNAs that suppress the translation of proteins involved in tumorigenesis and vascular function. Whether the adverse effects of statins may also have an epigenetic component has been less widely studied, although there is evidence that microRNA expression may be altered in statin-induced muscle and liver damage. As epigenetics and microRNAs influence gene expression, these changes could contribute to the pleiotropic and adverse effects of statins and have long-lasting effects on the health of statin users. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Pleiotropic Roles of the Msi1-Like Protein Msl1 in Cryptococcus neoformans

    PubMed Central

    Yang, Dong-Hoon; Maeng, Shinae; Strain, Anna K.; Floyd, Anna; Nielsen, Kirsten; Heitman, Joseph

    2012-01-01

    Msi1-like (MSIL) proteins contain WD40 motifs and have a pleiotropic cellular function as negative regulators of the Ras/cyclic AMP (cAMP) pathway and components of chromatin assembly factor 1 (CAF-1), yet they have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which causes life-threatening meningoencephalitis in humans. Notably, Msl1 plays pleiotropic roles in C. neoformans in both cAMP-dependent and -independent manners largely independent of Ras. Msl1 negatively controls antioxidant melanin production and sexual differentiation, and this was repressed by the inhibition of the cAMP-signaling pathway. In contrast, Msl1 controls thermotolerance, diverse stress responses, and antifungal drug resistance in a Ras/cAMP-independent manner. Cac2, which is the second CAF-1 component, appears to play both redundant and distinct functions compared to the functions of Msl1. Msl1 is required for the full virulence of C. neoformans. Transcriptome analysis identified a group of Msl1-regulated genes, which include stress-related genes such as HSP12 and HSP78. In conclusion, this study demonstrates pleiotropic roles of Msl1 in the human fungal pathogen C. neoformans, providing insight into a potential novel antifungal therapeutic target. PMID:23042129

  3. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore) Cattle Are Modulators of Growth.

    PubMed

    G T Pereira, Anirene; Utsunomiya, Yuri T; Milanesi, Marco; Torrecilha, Rafaela B P; Carmo, Adriana S; Neves, Haroldo H R; Carvalheiro, Roberto; Ajmone-Marsan, Paolo; Sonstegard, Tad S; Sölkner, Johann; Contreras-Castillo, Carmen J; Garcia, José F

    2016-01-01

    Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS), were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore) cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV) for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1) as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1), IGF2 (insulin like growth factor 2), GH1 (growth hormone 1), IGF1R (insulin like growth factor 1 receptor) and GHR (growth hormone receptor), suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway.

  4. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore) Cattle Are Modulators of Growth

    PubMed Central

    Milanesi, Marco; Torrecilha, Rafaela B. P.; Carmo, Adriana S.; Neves, Haroldo H. R.; Carvalheiro, Roberto; Ajmone-Marsan, Paolo; Sonstegard, Tad S.; Sölkner, Johann; Contreras-Castillo, Carmen J.; Garcia, José F.

    2016-01-01

    Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS), were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore) cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV) for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1) as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1), IGF2 (insulin like growth factor 2), GH1 (growth hormone 1), IGF1R (insulin like growth factor 1 receptor) and GHR (growth hormone receptor), suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway. PMID:27410030

  5. Derivation of a Bayes factor to distinguish between linked or pleiotropic quantitative trait loci.

    PubMed Central

    Varona, L; Gómez-Raya, L; Rauw, W M; Clop, A; Ovilo, C; Noguera, J L

    2004-01-01

    A simple procedure to calculate the Bayes factor between linked and pleiotropic QTL models is presented. The Bayes factor is calculated from the marginal prior and posterior densities of the locations of the QTL under a linkage and a pleiotropy model. The procedure is computed with a Gibbs sampler, and it can be easily applied to any model including the location of the QTL as a variable. The procedure was compared with a multivariate least-squares method. The proposed procedure showed better results in terms of power of detection of linkage when low information is available. As information increases, the performance of both procedures becomes similar. An example using data provided by an Iberian by Landrace pig intercross is presented. The results showed that three different QTL segregate in SSC6: a pleiotropic QTL affects myristic, palmitic, and eicosadienoic fatty acids; another pleiotropic QTL affects palmitoleic, stearic, and vaccenic fatty acids; and a third QTL affects the percentage of linoleic acid. In the example, the Bayes factor approach was more powerful than the multivariate least-squares approach. PMID:15020485

  6. Malaria Parasite-Infected Erythrocytes Secrete PfCK1, the Plasmodium Homologue of the Pleiotropic Protein Kinase Casein Kinase 1

    PubMed Central

    Dorin-Semblat, Dominique; Demarta-Gatsi, Claudia; Hamelin, Romain; Armand, Florence; Carvalho, Teresa Gil; Moniatte, Marc; Doerig, Christian

    2015-01-01

    Casein kinase 1 (CK1) is a pleiotropic protein kinase implicated in several fundamental processes of eukaryotic cell biology. Plasmodium falciparum encodes a single CK1 isoform, PfCK1, that is expressed at all stages of the parasite’s life cycle. We have previously shown that the pfck1 gene cannot be disrupted, but that the locus can be modified if no loss-of-function is incurred, suggesting an important role for this kinase in intra-erythrocytic asexual proliferation. Here, we report on the use of parasite lines expressing GFP- or His-tagged PfCK1 from the endogenous locus to investigate (i) the dynamics of PfCK1 localisation during the asexual cycle in red blood cells, and (ii) potential interactors of PfCK1, so as to gain insight into the involvement of the enzyme in specific cellular processes. Immunofluorescence analysis reveals a dynamic localisation of PfCK1, with evidence for a pool of the enzyme being directed to the membrane of the host erythrocyte in the early stages of infection, followed by a predominantly intra-parasite localisation in trophozoites and schizonts and association with micronemes in merozoites. Furthermore, we present strong evidence that a pool of enzymatically active PfCK1 is secreted into the culture supernatant, demonstrating that PfCK1 is an ectokinase. Our interactome experiments and ensuing kinase assays using recombinant PfCK1 to phosphorylate putative interactors in vitro suggest an involvement of PfCK1 in many cellular processes such as mRNA splicing, protein trafficking, ribosomal, and host cell invasion. PMID:26629826

  7. Which Sry locus is the hypertensive Y chromosome locus?

    PubMed

    Turner, Monte E; Farkas, Joel; Dunmire, Jeff; Ely, Daniel; Milsted, Amy

    2009-02-01

    The Y chromosome of the spontaneously hypertensive rat (SHR) contains a genetic component that raises blood pressure compared with the Wistar-Kyoto (WKY) Y chromosome. This research tests the Sry gene complex as the hypertensive component of the SHR Y chromosome. The Sry loci were sequenced in 1 strain with a hypertensive Y chromosome (SHR/Akr) and 2 strains with a normotensive Y chromosome (SHR/Crl and WKY/Akr). Both SHR strains have 7 Sry loci, whereas the WKY strain has 6. The 6 loci in common between SHR and WKY strains were identical in the sequence compared (coding region, 392-bp 5' prime flanking, 1200-bp 3' flanking). Both SHR strains have a locus (Sry3) not found in WKY rats, but this locus is different between SHR/Akr and SHR/Crl rats. Six mutations have accumulated in Sry3 between the SHR strains, whereas the other 6 Sry loci are identical. This pattern of an SHR-specific locus and mutation in this locus in SHR/Crl coinciding with the loss of Y chromosome hypertension is an expected pattern if Sry3 is the Y chromosome-hypertensive component. The SHR/y strain showed a significant increase in total Sry expression in the kidney between 4 and 15 weeks of age. There are significant differences in Sry expression between adrenal glands and the kidney (15 to 30 times higher in kidneys) but no significant differences between strains. These results, along with previous studies demonstrating an interaction of Sry with the tyrosine hydroxylase promoter and increased blood pressure with exogenous Sry expression, suggest the Sry loci as the hypertensive component of the SHR Y chromosome.

  8. A yigP mutant strain is a small colony variant of E. coli, and shows pleiotropic antibiotic resistance.

    PubMed

    Xia, Hui; Tang, Qiongwei; Song, Jie; Ye, Jiang; Wu, Haizhen; Zhang, Huizhan

    2017-09-15

    Small colony variants (SCVs) are a commonly observed subpopulation of bacteria that have a small colony size and distinctive biochemical characteristics. SCVs are more resistant to some antibiotics than the wild-type, and usually cause persistent infections in the clinic. SCV studies have been very active during the past two decades, especially of Staphylococcus aureus. However, fewer studies on Escherichia coli SCVs exist, so we studied an E. coli SCV during an experiment involving the deletion of the yigP locus. PCR and DNA sequencing revealed that the SCV was attributable to a defect in the yigP function. Furthermore, we investigated the antibiotic resistance profile of the SCV and it showed increased erythromycin, kanamycin and D-cycloserine resistance, but collateral sensitivity to ampicillin, polymyxin, chloramphenicol, tetracycline, rifampin, and nalidixic acid. We tried to determine the association between yigP and the pleiotropic antibiotic resistance of the SCV by analyzing biofilm formation, cellular morphology and coenzyme Q (Q8) production. Our results indicated that impaired Q8 biosynthesis was the primary factor that contributed to the increased resistance and collateral sensitivity of the SCV. This study offers a novel genetic basis for E. coli SCVs and an insight into the development of alternative antimicrobial strategies for clinical therapy.

  9. Caveolin Contributes to the Modulation of Basal and β-Adrenoceptor Stimulated Function of the Adult Rat Ventricular Myocyte by Simvastatin: A Novel Pleiotropic Effect

    PubMed Central

    Agarwal, Shailesh R.; Harvey, Robert D.; Porter, Karen E.; Calaghan, Sarah

    2014-01-01

    The number of people taking statins is increasing across the globe, highlighting the importance of fully understanding statins' effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (‘pleiotropic effects’). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 µM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2+]i) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16 and troponin I at Ser23/24 was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered β-adrenoceptor signalling. In addition

  10. Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac ▿

    PubMed Central

    van Leeuwen, Jolanda S.; Vermeulen, Nico P. E.; Vos, J. Chris

    2011-01-01

    Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p. PMID:21724882

  11. Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality

    PubMed Central

    Kulminski, Alexander M.; He, Liang; Culminskaya, Irina; Loiko, Elena; Arbeeva, Liubov; Bagley, Olivia; Yashkin, Arseniy; Fang, Fang; Ukraintseva, Svetlana V.; Wu, Deqing; Yashin, Anatoliy I.

    2016-01-01

    Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10−9), CHD by 35% (p = 8.9×10−6), HF by 55% (p = 9.7×10−5), stroke by 25% (p = 4.0×10−2), and ND by 100% (p = 1.3×10−3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10−21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality. PMID:27832070

  12. Speaking rate effects on locus equation slope

    PubMed Central

    Berry, Jeff; Weismer, Gary

    2013-01-01

    A locus equation describes a 1st order regression fit to a scatter of vowel steady-state frequency values predicting vowel onset frequency values. Locus equation coefficients are often interpreted as indices of coarticulation. Speaking rate variations with a constant consonant–vowel form are thought to induce changes in the degree of coarticulation. In the current work, the hypothesis that locus slope is a transparent index of coarticulation is examined through the analysis of acoustic samples of large-scale, nearly continuous variations in speaking rate. Following the methodological conventions for locus equation derivation, data pooled across ten vowels yield locus equation slopes that are mostly consistent with the hypothesis that locus equations vary systematically with coarticulation. Comparable analyses between different four-vowel pools reveal variations in the locus slope range and changes in locus slope sensitivity to rate change. Analyses across rate but within vowels are substantially less consistent with the locus hypothesis. Taken together, these findings suggest that the practice of vowel pooling exerts a non-negligible influence on locus outcomes. Results are discussed within the context of articulatory accounts of locus equations and the effects of speaking rate change. PMID:24535890

  13. Speaking rate effects on locus equation slope.

    PubMed

    Berry, Jeff; Weismer, Gary

    2013-11-01

    A locus equation describes a 1st order regression fit to a scatter of vowel steady-state frequency values predicting vowel onset frequency values. Locus equation coefficients are often interpreted as indices of coarticulation. Speaking rate variations with a constant consonant-vowel form are thought to induce changes in the degree of coarticulation. In the current work, the hypothesis that locus slope is a transparent index of coarticulation is examined through the analysis of acoustic samples of large-scale, nearly continuous variations in speaking rate. Following the methodological conventions for locus equation derivation, data pooled across ten vowels yield locus equation slopes that are mostly consistent with the hypothesis that locus equations vary systematically with coarticulation. Comparable analyses between different four-vowel pools reveal variations in the locus slope range and changes in locus slope sensitivity to rate change. Analyses across rate but within vowels are substantially less consistent with the locus hypothesis. Taken together, these findings suggest that the practice of vowel pooling exerts a non-negligible influence on locus outcomes. Results are discussed within the context of articulatory accounts of locus equations and the effects of speaking rate change.

  14. Definition of a consensus DNA-binding site for the Escherichia coli pleiotropic regulatory protein, FruR.

    PubMed

    Nègre, D; Bonod-Bidaud, C; Geourjon, C; Deléage, G; Cozzone, A J; Cortay, J C

    1996-07-01

    The FruR regulator of Escherichia coli controls the initiation of transcription of several operons encoding a variety of proteins involved in carbon and energy metabolism. The sequence determinants of the FruR-binding site were analysed by using 6x His-tagged FruR and a series of double-stranded randomized oligonucleotides. FruR consensus binding sites were selected and characterized by several consecutive rounds of the polymerase chain reaction-assisted binding-site selection method (BSS) using nitrocellulose-immobilized DNA-binding protein. FruR was demonstrated to require, for binding, an 8 bp left half-site motif and a 3 bp conserved right half-site with the following sequence: 5'-GNNGAATC/GNT-3'. In this sequence, the left half-site AATC/ consensus tetranucleotide is a typical motif of the DNA-binding site of the regulators of the GalR-Lacl family. On the other hand, the high degree of degeneracy found in the right half-site of this palindrome-like structure indicated that FruR, which is a tetramer in solution, interacts asymmetrically with the two half-sites of its operator. However, potentially FruR-target sites showing a high degree of symmetry were detected in 13 genes/operons. Among these, we have focused our interest on the pfkA gene, encoding phosphofructo-kinase-1, which is negatively regulated by FruR.

  15. The RNA chaperone Hfq is involved in stress response and virulence in Neisseria meningitidis and is a pleiotropic regulator of protein expression.

    PubMed

    Fantappiè, Laura; Metruccio, Matteo M E; Seib, Kate L; Oriente, Francesca; Cartocci, Elena; Ferlicca, Francesca; Giuliani, Marzia M; Scarlato, Vincenzo; Delany, Isabel

    2009-05-01

    The well-conserved protein Hfq has emerged as the key modulator of riboregulation in bacteria. This protein is thought to function as an RNA chaperone and to facilitate base pairing between small regulatory RNA (sRNA) and mRNA targets, and many sRNAs are dependent on the Hfq protein for their regulatory functions. To address the possible role of Hfq in riboregulated circuits in Neisseria meningitidis, we generated an Hfq mutant of the MC58 strain, and the knockout mutant has pleiotropic phenotypes; it has a general growth phenotype in vitro in culture media, and it is sensitive to a wide range of stresses, including those that it may encounter in the host. Furthermore, the expression profile of a vast number of proteins is clearly altered in the mutant, and we have identified 27 proteins by proteomics. All of the phenotypes tested to date are also restored by complementation of Hfq expression in the mutant strain. Importantly, in ex vivo and in vivo models of infection the Hfq mutant is attenuated. These data indicate that Hfq plays a key role in stress response and virulence, and we propose a major role for Hfq in regulation of gene expression. Moreover, this study suggests that in meningococcus there is a large Hfq-mediated sRNA network which so far is largely unexplored.

  16. The pleiotropic transcriptional regulator NlpR contributes to the modulation of nitrogen metabolism, lipogenesis and triacylglycerol accumulation in oleaginous rhodococci.

    PubMed

    Hernández, Martín A; Lara, Julia; Gago, Gabriela; Gramajo, Hugo; Alvarez, Héctor M

    2017-01-01

    The regulatory mechanisms involved in lipogenesis and triacylglycerol (TAG) accumulation are largely unknown in oleaginous rhodococci. In this study a regulatory protein (here called NlpR: Nitrogen lipid Regulator), which contributes to the modulation of nitrogen metabolism, lipogenesis and triacylglycerol accumulation in oleaginous rhodococci was identified. Under nitrogen deprivation conditions, in which TAG accumulation is stimulated, the nlpR gene was significantly upregulated, whereas a significant decrease of its expression and TAG accumulation occurred when cerulenin was added. The nlpR disruption negatively affected the nitrate/nitrite reduction as well as lipid biosynthesis under nitrogen-limiting conditions. In contrast, its overexpression increased TAG production during cultivation of cells in nitrogen-rich media. A putative 'NlpR-binding motif' upstream of several genes related to nitrogen and lipid metabolisms was found. The nlpR disruption in RHA1 strain led to a reduced transcription of genes involved in nitrate/nitrite assimilation, as well as in fatty acid and TAG biosynthesis. Purified NlpR was able to bind to narK, nirD, fasI, plsC and atf3 promoter regions. It was suggested that NlpR acts as a pleiotropic transcriptional regulator by activating of nitrate/nitrite assimilation genes and others genes involved in fatty acid and TAG biosynthesis, in response to nitrogen deprivation.

  17. Pleiotropic Control of Secondary Metabolism and Morphological Development by KsbC, a Butyrolactone Autoregulator Receptor Homologue in Kitasatospora setae

    PubMed Central

    Aroonsri, Aiyada; Kitani, Shigeru; Hashimoto, Junko; Kosone, Ikuko; Izumikawa, Miho; Komatsu, Mamoru; Fujita, Nobuyuki; Takahashi, Yoko; Shin-ya, Kazuo; Ikeda, Haruo

    2012-01-01

    The γ-butyrolactone autoregulator signaling cascades have been shown to control secondary metabolism and/or morphological development among many Streptomyces species. However, the conservation and variation of the regulatory systems among actinomycetes remain to be clarified. The genome sequence of Kitasatospora setae, which also belongs to the family Streptomycetaceae containing the genus Streptomyces, has revealed the presence of three homologues of the autoregulator receptor: KsbA, which has previously been confirmed to be involved only in secondary metabolism; KsbB; and KsbC. We describe here the characterization of ksbC, whose regulatory cluster closely resembles the Streptomyces virginiae barA locus responsible for the autoregulator signaling cascade. Deletion of the gene ksbC resulted in lowered production of bafilomycin and a defect of aerial mycelium formation, together with the early and enhanced production of a novel β-carboline alkaloid named kitasetaline. A putative kitasetaline biosynthetic gene cluster was identified, and its expression in a heterologous host led to the production of kitasetaline together with JBIR-133, the production of which is also detected in the ksbC disruptant, and JBIR-134 as novel β-carboline alkaloids, indicating that these genes were biosynthetic genes for β-carboline alkaloid and thus are the first such genes to be discovered in bacteria. PMID:22961899

  18. Genomic characterization of the Atlantic cod sex-locus

    PubMed Central

    Star, Bastiaan; Tørresen, Ole K.; Nederbragt, Alexander J.; Jakobsen, Kjetill S.; Pampoulie, Christophe; Jentoft, Sissel

    2016-01-01

    A variety of sex determination mechanisms can be observed in evolutionary divergent teleosts. Sex determination is genetic in Atlantic cod (Gadus morhua), however the genomic location or size of its sex-locus is unknown. Here, we characterize the sex-locus of Atlantic cod using whole genome sequence (WGS) data of 227 wild-caught specimens. Analyzing more than 55 million polymorphic loci, we identify 166 loci that are associated with sex. These loci are located in six distinct regions on five different linkage groups (LG) in the genome. The largest of these regions, an approximately 55 Kb region on LG11, contains the majority of genotypes that segregate closely according to a XX-XY system. Genotypes in this region can be used genetically determine sex, whereas those in the other regions are inconsistently sex-linked. The identified region on LG11 and its surrounding genes have no clear sequence homology with genes or regulatory elements associated with sex-determination or differentiation in other species. The functionality of this sex-locus therefore remains unknown. The WGS strategy used here proved adequate for detecting the small regions associated with sex in this species. Our results highlight the evolutionary flexibility in genomic architecture underlying teleost sex-determination and allow practical applications to genetically sex Atlantic cod. PMID:27499266

  19. Pleiotropy constrains the evolution of protein but not regulatory sequences in a transcription regulatory network influencing complex social behaviors

    PubMed Central

    Molodtsova, Daria; Harpur, Brock A.; Kent, Clement F.; Seevananthan, Kajendra; Zayed, Amro

    2014-01-01

    It is increasingly apparent that genes and networks that influence complex behavior are evolutionary conserved, which is paradoxical considering that behavior is labile over evolutionary timescales. How does adaptive change in behavior arise if behavior is controlled by conserved, pleiotropic, and likely evolutionary constrained genes? Pleiotropy and connectedness are known to constrain the general rate of protein evolution, prompting some to suggest that the evolution of complex traits, including behavior, is fuelled by regulatory sequence evolution. However, we seldom have data on the strength of selection on mutations in coding and regulatory sequences, and this hinders our ability to study how pleiotropy influences coding and regulatory sequence evolution. Here we use population genomics to estimate the strength of selection on coding and regulatory mutations for a transcriptional regulatory network that influences complex behavior of honey bees. We found that replacement mutations in highly connected transcription factors and target genes experience significantly stronger negative selection relative to weakly connected transcription factors and targets. Adaptively evolving proteins were significantly more likely to reside at the periphery of the regulatory network, while proteins with signs of negative selection were near the core of the network. Interestingly, connectedness and network structure had minimal influence on the strength of selection on putative regulatory sequences for both transcription factors and their targets. Our study indicates that adaptive evolution of complex behavior can arise because of positive selection on protein-coding mutations in peripheral genes, and on regulatory sequence mutations in both transcription factors and their targets throughout the network. PMID:25566318

  20. Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease.

    PubMed

    Douvris, Adrianna; Soubeyrand, Sébastien; Naing, Thet; Martinuk, Amy; Nikpay, Majid; Williams, Andrew; Buick, Julie; Yauk, Carole; McPherson, Ruth

    2014-06-03

    The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid-associated single nucleotide polymorphisms (SNPs), identified by genome-wide association studies, are located ≈30 kb downstream from TRIB1, suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Characterization of the risk locus reveals that it encompasses a gene, TRIB1-associated locus (TRIBAL), composed of a well-conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high-density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome-wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. These studies demonstrate an interplay between a novel locus, TRIBAL, and TRIB1. TRIBAL is located in the genome-wide association studies identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression, and associates with plasma triglyceride concentrations. © 2014 The Authors. Published on behalf of the

  1. Suppression of pleiotropic phenotypes of a Burkholderia multivorans fur mutant by oxyR mutation.

    PubMed

    Kimura, Akane; Yuhara, Satoshi; Ohtsubo, Yoshiyuki; Nagata, Yuji; Tsuda, Masataka

    2012-05-01

    Fur (ferric uptake regulator) is an iron-responsive transcriptional regulator in many bacterial species, and the fur mutant of Burkholderia multivorans ATCC 17616 exhibits pleiotropic phenotypes, such as an inability to efficiently use several carbon sources, as well as high sensitivity to hydrogen peroxide (H(2)O(2)), paraquat (a superoxide-producing compound) and nitric oxide (NO). To gain more insight into the pleiotropic role of the Fur protein of ATCC 17616, spontaneous suppressor mutants of the ATCC 17616 fur mutant that restored tolerance to NO were isolated and characterized in this study. The microarray-based comparative genomic analysis and subsequent sequencing analysis indicated that such suppressor mutants had a 2 bp deletion in the oxyR gene, whose orthologues encode H(2)O(2)-responsive transcriptional regulators in other bacterial species. The suppressor mutants and the reconstructed fur-oxyR double-deletion mutant showed indistinguishable phenotypes in that they were all (i) more resistant than the fur mutant to H(2)O(2), superoxide, NO and streptonigrin (an iron-activated antibiotic) and (ii) able to use carbon sources that cannot efficiently support the growth of the fur mutant. These results clearly indicate that the oxyR mutation suppressed the pleiotropic effect of the B. multivorans fur mutant. The fur-oxyR double mutants were found to overexpress the KatG (catalase/peroxidase) and AhpC1 and AhpD (alkyl hydroperoxide reductase subunits C and D) proteins, and their enzymic activities to remove reactive oxygen and nitrogen species were suggested to be responsible for the suppression of phenotypes caused by the fur mutation.

  2. Lack of pleiotropic genetic effects between adiposity and sex hormone-binding globulin concentrations before and after 20 weeks of exercise training: the HERITAGE family study.

    PubMed

    Feitosa, Mary F; Borecki, Ingrid B; Rankinen, Tuomo; Leon, Arthur S; Skinner, James S; Wilmore, Jack H; Bouchard, Claude; Rao, D C

    2003-01-01

    The relationship between sex hormone-binding globulin (SHBG) concentrations and body fat accumulation and distribution is governed by complex dynamic factors, which may involve common genetic and/or environmental factors. The current study investigated the genetic and environmental basis for the correlation between SHBG and body fat. Several measures of adiposity were investigated including body mass index (BMI) and a trunk to extremity skinfold thickness ratio (TER) assessed by anthropometry, body composition measured by hydrostatic weighing (total body fat mass [FM], fat-free mass [FFM], and percent body fat [%BF]), and abdominal fat measured by computerized tomography scanning (abdominal visceral fat [AVF]). The study comprised 501 white subjects from 99 families and 277 black subjects from 117 families participating in the HERITAGE Family Study. Familial correlations between traits and their cosegregation were investigated both at baseline and in response to endurance exercise training. Significant inverse phenotypic correlations were detected in both races between SHBG and adiposity measures at baseline and also in response to training. Significant cross-trait familial resemblance was found between SHBG and both BMI and FFM at baseline that accounted for 11% and 4% of maximal heritability, respectively, in white families. However, a joint segregation analysis of the traits failed to implicate shared genetic effects. Specifically, neither a pleiotropic major locus nor pleiotropic polygenic effects were detected between SHBG and BMI or FFM. A maximal cross-trait heritability of 45% was obtained for SHBG and TER at baseline in black families. However, no firm conclusions as to the etiology of this relationship could be drawn because of the limitations of small sample size. For the training response phenotypes, there was no significant cross-trait correlation between SHBG and any adiposity measures studied here, suggesting that their correlation may have an

  3. Distal Regions of the Human IFNG Locus Direct Cell Type-Specific Expression

    PubMed Central

    Collins, Patrick L.; Chang, Shaojing; Henderson, Melodie; Soutto, Mohammed; Davis, Georgia M.; McLoed, Allyson G.; Townsend, Michael J.; Glimcher, Laurie H.; Mortlock, Douglas P.; Aune, Thomas M.

    2010-01-01

    Genes, such as IFNG, which are expressed in multiple cell lineages of the immune system, may employ a common set of regulatory elements to direct transcription in multiple cell types or individual regulatory elements to direct expression in individual cell lineages. By employing a bacterial artificial chromosome transgenic system, we demonstrate that IFNG employs unique regulatory elements to achieve lineage-specific transcriptional control. Specifically, a one 1-kb element 30 kb upstream of IFNG activates transcription in T cells and NKT cells but not in NK cells. This distal regulatory element is a Runx3 binding site in Th1 cells and is needed for RNA polymerase II recruitment to IFNG, but it is not absolutely required for histone acetylation of the IFNG locus. These results support a model whereby IFNG utilizes cis-regulatory elements with cell type-restricted function. PMID:20574006

  4. EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts.

    PubMed

    Fan, Jian-Bo; Liu, Wei; Zhu, Xin-Hui; Yuan, Kun; Xu, Da-Wei; Chen, Jia-Jia; Cui, Zhi-Ming

    2015-01-01

    Epidermal growth factor (EGF) receptor (EGFR) emerges as an essential molecule for the regulating of osteoblast cellular functions. In the current study, we explored the effect of epiregulin, a new EGFR ligand, on osteoblast functions in vitro, and studied the underlying mechanisms. We found that epiregulin-induced EGFR activation in both primary osteoblasts and osteoblast-like MC3T3-E1 cells. Meanwhile, epiregulin activated AKT-mammalian target of rapamycin (mTOR) and Erk-mitogen-activated protein kinase (MAPK) signalings in cultured osteoblasts, which were blocked by EGFR inhibitor AG1478 or monoclonal antibody against EGFR (anti-EGFR). Further, in primary and MC3T3-E1 osteoblasts, epiregulin promoted cell proliferation and increased alkaline phosphatase activity, while inhibiting dexamethasone (Dex)-induced cell death. Such effects by epiregulin were largely inhibited by AG1478 or anti-EGFR. Notably, AKT-mTOR inhibitors, but not Erk inhibitors, alleviated epiregulin-induced above pleiotropic functions in osteoblasts. Meanwhile, siRNA depletion of Sin1, a key component of mTOR complex 2 (mTORC2), also suppressed epiregulin-exerted effects in MC3T3-E1 cells. Together, these results suggest that epiregulin-induced pleiotropic functions in cultured osteoblasts are mediated through EGFR-AKT-mTOR signalings.

  5. Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study.

    PubMed

    Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

    2016-01-01

    Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research.

  6. Heritability of floral volatiles and pleiotropic responses to artificial selection in Brassica rapa.

    PubMed

    Zu, Pengjuan; Blanckenhorn, Wolf U; Schiestl, Florian P

    2016-02-01

    The evolution of the vast diversity of floral volatiles is little understood, although they serve fundamental functions, such as pollinator attraction and herbivore deterrence. Floral volatiles are often species specific, yet highly variable and sensitive to environmental factors. To date, nothing is known about the heritability of floral volatiles, and whether individual compounds can evolve independently or solely in concert with the whole volatile bouquet. We conducted bi-directional artificial selection on four target floral volatiles to estimate heritability and correlated pleiotropic responses in the wild turnip (Brassica rapa). The realized heritability of the four target volatiles ranged from 20% to 45%. The average narrow-sense heritability of all 13 analyzed floral volatiles was 18% based on parent-offspring regressions. There were pleiotropic effects of the selected floral volatile compounds on other constituents of the floral scent bouquet, on flowering time and on some morphological traits. We found that the whole floral scent bouquet changed, even when there was selection only on single compounds, with the overall phenotypic covariance being unaffected. Our study demonstrates that floral scent can evolve rapidly under phenotypic selection, but with additional correlated responses in traits that are not direct targets of selection. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  7. Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases

    PubMed Central

    Russell, Shirley B.; Smith, Joan C.; Huang, Minjun; Trupin, Joel S.; Williams, Scott M.

    2015-01-01

    Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases. PMID:26540410

  8. The pleiotropic allatoregulatory neuropeptides and their receptors: A mini-review.

    PubMed

    Verlinden, Heleen; Gijbels, Marijke; Lismont, Els; Lenaerts, Cynthia; Vanden Broeck, Jozef; Marchal, Elisabeth

    2015-09-01

    Juvenile hormones (JH) are highly pleiotropic insect hormones essential for post-embryonic development. The circulating JH titer in the hemolymph of insects is influenced by enzymatic degradation, binding to JH carrier proteins, uptake and storage in target organs, but evidently also by rates of production at its site of synthesis, the corpora allata (CA). The multiple processes in which JH is involved alongside the critical significance of JH in insect development emphasize the importance for elucidating the control of JH production. Production of JH in CA cells is regulated by different factors: by neurotransmitters, such as dopamine and glutamate, but also by allatoregulatory neuropeptides originating from the brain and axonally transported to the CA where they bind to their G protein-coupled receptors (GPCRs). Different classes of allatoregulatory peptides exist which have other functions aside from acting as influencers of JH production. These pleiotropic neuropeptides regulate different processes in different insect orders. In this mini-review, we will give an overview of allatotropins and allatostatins, and their recently characterized GPCRs with a view to better understand their modes of action and different action sites. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering.

    PubMed

    Marzilli, Mario

    2010-01-01

    Evidence is mounting that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a number of pleiotropic effects over and above their lipid-lowering properties in patients with cardiovascular disease and heart failure. In addition to lowering low-density lipoprotein cholesterol and triglyceride levels, several studies have shown statins to improve survival and reduce the risk of major cardiovascular events in patients without established cardiovascular disease but with cardiovascular risk factors. Statins have also been shown to have beneficial effects, including a reduction in all-cause mortality, in patients with ischemic and non-ischemic congestive heart failure, and have been associated with a reduced incidence of atrial fibrillation. Furthermore, statins have been associated with improvements in renal function in patients with pre-existing renal disease or the prevention of new-onset renal dysfunction, as well as improvements in lung function in patients with chronic obstructive pulmonary disease or age-related decline in lung function. The pleiotropic effects of statins appear to result from improvements in endothelial function, a reduction in inflammatory mediators, a decline in the development of atheroma through the stabilization of atheromatous plaques, and the inhibition of cardiac hypertrophy through an antioxidant mechanism. Long-term statin use may reduce morbidity and mortality rates in a broad range of patients, and most patients at high risk of cardiovascular disease may benefit from statin treatment; however, further data are required to demonstrate conclusively whether these trends are truly independent of the lipid-lowering effects of statins.

  10. Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study

    PubMed Central

    Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

    2016-01-01

    Background: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Methods: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. Results: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Conclusion: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research. PMID:27536242

  11. Pleiotropic Effects of Long-term Monotherapy with Rosuvastatin in Dogs with Moderate Heart Failure

    PubMed Central

    Zacà, Valerio; Mishra, Sudhish; Gupta, Ramesh C.; Rastogi, Sharad; Sabbah, Hani N.

    2013-01-01

    Objective The objective of this study was to investigate potential pleiotropic effects of rosuvastatin (RSV) in left ventricular (LV) myocardium of dogs with moderate heart failure (HF). Methods LV tissue was obtained from HF dogs randomized to 3 months therapy with low dose (LD) RSV (n=7), high dose (HD) RSV (n=7) or to no therapy (Control, n=7), and from 7 normal (NL) dogs. mRNA and protein expression of pro-hypertrophic mediators NGFI-A binding protein 1 (Nab1), phosphatase and tensin homolog (PTEN), phosphoinositide-3 kinase (PI3K) and mammalian target of rapamycin (mTOR); pro-inflammatory cytokine interleukin-6 (IL-6); bone marrow-derived stem cells (BMSCs) markers cKit and Sca1; vascular endothelial (VEGF) and fibroblast (FGF) growth factors and nitric oxide synthase (NOS) isoforms were measured. Results Nab1, PTEN, PI3K, mTOR, and IL-6 increased in Controls. HD RSV reduced expression of Nab1, PTEN, PI3K, mTOR, and IL-6 to near normal levels. cKit and Sca1 significantly increased while VEGF and FGF decreased in Controls compared to NL. RSV therapy further increased expression of cKit, Sca1, VEGF and FGF. HD RSV normalized expression of NOS isoforms. Conclusion These pleiotropic effects of RSV may account, in part, for the observed beneficial effect of RSV on LV function and structural remodeling. PMID:23128666

  12. Factors Determining Adolescent Locus of Control.

    ERIC Educational Resources Information Center

    Kopera-Frye, Karen F.; And Others

    Previous research has demonstrated an association between locus of control in adolescence and a successful transition to adulthood. Having an external locus of control has been implicated as an important factor in adolescent behaviors such as teenage pregnancy and delinquency, and has been found to be negatively related to school achievement. This…

  13. Rates of molecular evolution vary in vertebrates for insulin-like growth factor-1 (IGF-1), a pleiotropic locus that regulates life history traits.

    PubMed

    Sparkman, Amanda M; Schwartz, Tonia S; Madden, Jill A; Boyken, Scott E; Ford, Neil B; Serb, Jeanne M; Bronikowski, Anne M

    2012-08-01

    Insulin-like growth factor-1 (IGF-1) is a member of the vertebrate insulin/insulin-like growth factor/relaxin gene family necessary for growth, reproduction, and survival at both the cellular and organismal level. Its sequence, protein structure, and function have been characterized in mammals, birds, and fish; however, a notable gap in our current knowledge of the function of IGF-1 and its molecular evolution is information in ectothermic reptiles. To address this disparity, we sequenced the coding region of IGF-1 in 11 reptile species-one crocodilian, three turtles, three lizards, and four snakes. Complete sequencing of the full mRNA transcript of a snake revealed the Ea-isoform, the predominant isoform of IGF-1 also reported in other vertebrate groups. A gene tree of the IGF-1 protein-coding region that incorporated sequences from diverse vertebrate groups showed similarity to the species phylogeny, with the exception of the placement of Testudines as sister group to Aves, due to their high nucleotide sequence similarity. In contrast, long-branch lengths indicate more rapid divergence in IGF-1 among lizards and snakes. Additionally, lepidosaurs (i.e., lizards and snakes) had higher rates of non-synonymous:synonymous substitutions (dN/dS) relative to archosaurs (i.e., birds and crocodilians) and turtles. Tests for positive selection on specific codons within branches and evaluation of the changes in the amino acid properties, suggested positive selection in lepidosaurs on the C domain of IGF-1, which is involved in binding affinity to the IGF-1 receptor. Predicted structural changes suggest that major alterations in protein structure and function may have occurred in reptiles. These data propose new insights into the molecular co-evolution of IGF-1 and its receptors, and ultimately the evolution of IGF-1's role in regulating life-history traits across vertebrates.

  14. Regulatory Forum.

    PubMed

    Peden, W Michael

    2016-12-01

    Revision of the International Council for Harmonization (ICH) S1 guidance for rat carcinogenicity studies to be more selective of compounds requiring a 2-year rat carcinogenicity study has been proposed following extensive evaluation of rat carcinogenicity and chronic toxicity studies by industry and drug regulatory authorities. To inform the ICH S1 expert working group in their potential revision of ICH S1, a prospective evaluation study was initiated in 2013, in which sponsors would assess the pharmacologic and toxicologic findings present in the chronic toxicity studies and predict a positive or negative carcinogenicity outcome using a weight of evidence argument (a carcinogenicity assessment document [CAD]). The Scientific and Regulatory Policy Committee was asked by the Society of Toxicology Pathology (STP) executive committee to track these changes with ICH S1 and inform the STP membership of status changes. This commentary is intended to provide a brief summary of recent changes to the CAD guidance and highlight the importance of STP membership participation in the process of CAD submissions.

  15. Structure of the MHC A and B locus promoters in hominoids

    SciTech Connect

    Vallejo, A.N.; Pease, L.R.

    1995-04-15

    The expansion and contraction of mammalian class I multigene families raises the issue as to what determines the loss or retention of family members. We propose that accumulating changes in regulatory regions result in the loss of expression of the gene products during times critical to selection, leading to the extinction of misregulated genes. The structures of promoter regions of MHC class I genes in nonhuman primates support this view. The B promoters are more homogeneous and contain regulatory elements also found in the promoters of the homologous class I genes of more distant mammals, whereas the A locus promoters were significantly more heterogeneous, have fewer sequence motifs related to known transcription factor-binding sites and have accumulated nucleotide substitutions within one of the widely conserved class I promoter elements. These findings are consistent with the view that the more polymorphic B locus is the principal MHC locus encoding functional class I Ag-presenting molecules whereas the less polymorphic A locus is assuming a secondary role as a consequence of promoter defects. 50 refs., 5 figs., 2 tabs.

  16. Characterization of the enhancer element of the Danio rerio minor globin gene locus.

    PubMed

    Nefedochkina, Anastasia V; Petrova, Natalia V; Ioudinkova, Elena S; Kovina, Anastasia P; Iarovaia, Olga V; Razin, Sergey V

    2016-04-01

    In Danio rerio, the alpha- and beta-globin genes are present in two clusters: a major cluster located on chromosome 3 and a minor cluster located on chromosome 12. In contrast to the segregated alpha- and beta-globin gene domains of warm-blooded animals, in Danio rerio, each cluster contains both alpha- and beta-globin genes. Expression of globin genes present in the major cluster is controlled by an erythroid-specific enhancer similar to the major regulatory element of mammalian and avian alpha-globin gene domains. The enhancer controlling expression of the globin genes present in the minor locus has not been identified yet. Based on the distribution of epigenetic marks, we have selected two genomic regions that might harbor an enhancer of the minor locus. Using transient transfection of constructs with a reporter gene, we have demonstrated that a ~500-bp DNA fragment located ~1.7 Kb upstream of the αe4 gene possesses an erythroid-specific enhancer active with respect to promoters present in both the major and the minor globin gene loci of Danio rerio. The identified enhancer element harbors clustered binding sites for GATA-1, NF-E2, and EKLF similar to the enhancer of the major globin locus on chromosome 3. Both enhancers appear to have emerged as a result of independent evolution of a duplicated regulatory element present in an ancestral single alpha-/beta-globin locus that existed before teleost-specific genome duplication.

  17. Determining the bistability parameter ranges of artificially induced lac operon using the root locus method.

    PubMed

    Avcu, N; Alyürük, H; Demir, G K; Pekergin, F; Cavas, L; Güzeliş, C

    2015-06-01

    This paper employs the root locus method to conduct a detailed investigation of the parameter regions that ensure bistability in a well-studied gene regulatory network namely, lac operon of Escherichia coli (E. coli). In contrast to previous works, the parametric bistability conditions observed in this study constitute a complete set of necessary and sufficient conditions. These conditions were derived by applying the root locus method to the polynomial equilibrium equation of the lac operon model to determine the parameter values yielding the multiple real roots necessary for bistability. The lac operon model used was defined as an ordinary differential equation system in a state equation form with a rational right hand side, and it was compatible with the Hill and Michaelis-Menten approaches of enzyme kinetics used to describe biochemical reactions that govern lactose metabolism. The developed root locus method can be used to study the steady-state behavior of any type of convergent biological system model based on mass action kinetics. This method provides a solution to the problem of analyzing gene regulatory networks under parameter uncertainties because the root locus method considers the model parameters as variable, rather than fixed. The obtained bistability ranges for the lac operon model parameters have the potential to elucidate the appearance of bistability for E. coli cells in in vivo experiments, and they could also be used to design robust hysteretic switches in synthetic biology.

  18. TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits

    PubMed Central

    Diogo, Dorothée; Bastarache, Lisa; Liao, Katherine P.; Graham, Robert R.; Fulton, Robert S.; Greenberg, Jeffrey D.; Eyre, Steve; Bowes, John; Cui, Jing; Lee, Annette; Pappas, Dimitrios A.; Kremer, Joel M.; Barton, Anne; Coenen, Marieke J. H.; Franke, Barbara; Kiemeney, Lambertus A.; Mariette, Xavier; Richard-Miceli, Corrine; Canhão, Helena; Fonseca, João E.; de Vries, Niek; Tak, Paul P.; Crusius, J. Bart A.; Nurmohamed, Michael T.; Kurreeman, Fina; Mikuls, Ted R.; Okada, Yukinori; Stahl, Eli A.; Larson, David E.; Deluca, Tracie L.; O'Laughlin, Michelle; Fronick, Catrina C.; Fulton, Lucinda L.; Kosoy, Roman; Ransom, Michael; Bhangale, Tushar R.; Ortmann, Ward; Cagan, Andrew; Gainer, Vivian; Karlson, Elizabeth W.; Kohane, Isaac; Murphy, Shawn N.; Martin, Javier; Zhernakova, Alexandra; Klareskog, Lars; Padyukov, Leonid; Worthington, Jane; Mardis, Elaine R.; Seldin, Michael F.; Gregersen, Peter K.; Behrens, Timothy; Raychaudhuri, Soumya; Denny, Joshua C.; Plenge, Robert M.

    2015-01-01

    Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases. PMID:25849893

  19. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.

    PubMed

    Diogo, Dorothée; Bastarache, Lisa; Liao, Katherine P; Graham, Robert R; Fulton, Robert S; Greenberg, Jeffrey D; Eyre, Steve; Bowes, John; Cui, Jing; Lee, Annette; Pappas, Dimitrios A; Kremer, Joel M; Barton, Anne; Coenen, Marieke J H; Franke, Barbara; Kiemeney, Lambertus A; Mariette, Xavier; Richard-Miceli, Corrine; Canhão, Helena; Fonseca, João E; de Vries, Niek; Tak, Paul P; Crusius, J Bart A; Nurmohamed, Michael T; Kurreeman, Fina; Mikuls, Ted R; Okada, Yukinori; Stahl, Eli A; Larson, David E; Deluca, Tracie L; O'Laughlin, Michelle; Fronick, Catrina C; Fulton, Lucinda L; Kosoy, Roman; Ransom, Michael; Bhangale, Tushar R; Ortmann, Ward; Cagan, Andrew; Gainer, Vivian; Karlson, Elizabeth W; Kohane, Isaac; Murphy, Shawn N; Martin, Javier; Zhernakova, Alexandra; Klareskog, Lars; Padyukov, Leonid; Worthington, Jane; Mardis, Elaine R; Seldin, Michael F; Gregersen, Peter K; Behrens, Timothy; Raychaudhuri, Soumya; Denny, Joshua C; Plenge, Robert M

    2015-01-01

    Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.

  20. The Pleiotropic Role of the 26S Proteasome Subunit RPN10 in Arabidopsis Growth and Development Supports a Substrate-Specific Function in Abscisic Acid Signaling

    PubMed Central

    Smalle, Jan; Kurepa, Jasmina; Yang, Peizhen; Emborg, Thomas J.; Babiychuk, Elena; Kushnir, Sergei; Vierstra, Richard D.

    2003-01-01

    The 26S proteasome is an essential protease complex responsible for removing most short-lived intracellular proteins, especially those modified with polyubiquitin chains. We show here that an Arabidopsis mutant expressing an altered RPN10 subunit exhibited a pleiotropic phenotype consistent with specific changes in 26S proteasome function. rpn10-1 plants displayed reduced seed germination, growth rate, stamen number, genetic transmission through the male gamete, and hormone-induced cell division, which can be explained partially by a constitutive downregulation of the key cell cycle gene CDKA;1. rpn10-1 also was more sensitive to abscisic acid (ABA), salt, and sucrose stress and to DNA-damaging agents and had decreased sensitivity to cytokinin and auxin. Most of the phenotypes can be explained by a hypersensitivity to ABA, which is reflected at the molecular level by the selective stabilization of the short-lived ABA-signaling protein ABI5. Collectively, these results indicate that RPN10 affects a number of regulatory processes in Arabidopsis likely by directing specific proteins to the 26S proteasome for degradation. A particularly important role may be in regulating the responses to signals promulgated by ABA. PMID:12671091

  1. The pleiotropic role of the 26S proteasome subunit RPN10 in Arabidopsis growth and development supports a substrate-specific function in abscisic acid signaling.

    PubMed

    Smalle, Jan; Kurepa, Jasmina; Yang, Peizhen; Emborg, Thomas J; Babiychuk, Elena; Kushnir, Sergei; Vierstra, Richard D

    2003-04-01

    The 26S proteasome is an essential protease complex responsible for removing most short-lived intracellular proteins, especially those modified with polyubiquitin chains. We show here that an Arabidopsis mutant expressing an altered RPN10 subunit exhibited a pleiotropic phenotype consistent with specific changes in 26S proteasome function. rpn10-1 plants displayed reduced seed germination, growth rate, stamen number, genetic transmission through the male gamete, and hormone-induced cell division, which can be explained partially by a constitutive downregulation of the key cell cycle gene CDKA;1. rpn10-1 also was more sensitive to abscisic acid (ABA), salt, and sucrose stress and to DNA-damaging agents and had decreased sensitivity to cytokinin and auxin. Most of the phenotypes can be explained by a hypersensitivity to ABA, which is reflected at the molecular level by the selective stabilization of the short-lived ABA-signaling protein ABI5. Collectively, these results indicate that RPN10 affects a number of regulatory processes in Arabidopsis likely by directing specific proteins to the 26S proteasome for degradation. A particularly important role may be in regulating the responses to signals promulgated by ABA.

  2. Two Novel AP2/EREBP Transcription Factor Genes TaPARG Have Pleiotropic Functions on Plant Architecture and Yield-Related Traits in Common Wheat

    PubMed Central

    Li, Bo; Li, Qiaoru; Mao, Xinguo; Li, Ang; Wang, Jingyi; Chang, Xiaoping; Hao, Chenyang; Zhang, Xueyong; Jing, Ruilian

    2016-01-01

    AP2/EREBPs play significant roles in plant growth and development. A novel, pleiotropic TaPARG (PLANT ARCHITECTURE-RELATED GENE), a member of the AP2/EREBP transcription factor gene family, and its flanking sequences were isolated in wheat (Triticum aestivum L.). Two TaPARG genes were identified and named as TaPARG-2A and TaPARG-2D. Their amino acid sequences were highly similar especially in the functional domains. TaPARG-2A on chromosome 2A was flanked by markers Xwmc63 and Xgwm372. TaPARG-2D was mapped to chromosome 2D. Subcellular localization revealed that TaPARG-2D was localized in the nucleus. The results of tissue expression pattern, overexpression in rice, association analysis and distinct population verification jointly revealed that TaPARG functions during the entire growth cycle of wheat. Its functions include regulation of plant architecture-related and yield-related traits. Association analysis, geographic distribution and allelic frequencies suggested that favored haplotypes Hap-2A-2 and Hap-2A-3 were selected in Chinese wheat breeding programs. Both favored haplotypes might be caused by a single amino acid substitution (His/Tyr). These results suggest that TaPARG is a regulatory factor in plant growth and development, and that the favored alleles might be useful for improving plant architecture and grain yield of wheat. PMID:27555860

  3. Regulatory divergence modifies limb length between mammals

    PubMed Central

    Cretekos, Chris J.; Wang, Ying; Green, Eric D.; Martin, James F.; Rasweiler, John J.; Behringer, Richard R.

    2008-01-01

    Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation. We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls because of endochondral bone formation alterations. Surprisingly, deletion of the mouse Prx1 limb enhancer results in normal forelimb length and Prx1 expression, revealing regulatory redundancy. These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations. PMID:18198333

  4. Epigenetic genome mining of an endophytic fungus leads to the pleiotropic biosynthesis of natural products.

    PubMed

    Mao, Xu-Ming; Xu, Wei; Li, Dehai; Yin, Wen-Bing; Chooi, Yit-Heng; Li, Yong-Quan; Tang, Yi; Hu, Youcai

    2015-06-22

    The small-molecule biosynthetic potential of most filamentous fungi has remained largely unexplored and represents an attractive source for the discovery of new compounds. Genome sequencing of Calcarisporium arbuscula, a mushroom-endophytic fungus, revealed 68 core genes that are involved in natural product biosynthesis. This is in sharp contrast to the predominant production of the ATPase inhibitors aurovertin B and D in the wild-type fungus. Inactivation of a histone H3 deacetylase led to pleiotropic activation and overexpression of more than 75 % of the biosynthetic genes. Sampling of the overproduced compounds led to the isolation of ten compounds of which four contained new structures, including the cyclic peptides arbumycin and arbumelin, the diterpenoid arbuscullic acid A, and the meroterpenoid arbuscullic acid B. Such epigenetic modifications therefore provide a rapid and global approach to mine the chemical diversity of endophytic fungi. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Resveratrol induces ordered domains formation in biomembranes: Implication for its pleiotropic action.

    PubMed

    Neves, Ana Rute; Nunes, Cláudia; Reis, Salette

    2016-01-01

    Resveratrol is a polyphenol compound with great value in cancer therapy, cardiovascular protection, and neurodegenerative disorders. The mechanism by which resveratrol exerts such pleiotropic effects is not yet clear and there is a huge need to understand the influence of this compound on the regulation of lipid domains formation on membrane structure. The aim of the present study was to reveal potential molecular interactions between resveratrol and lipid rafts found in cell membranes by means of Förster resonance energy transfer, DPH fluorescence quenching, and triton X-100 detergent resistance assay. Liposomes composed of egg phosphatidylcholine, cholesterol, and sphingomyelin were used as model membranes. The results revealed that resveratrol induces phase separation and formation of liquid-ordered domains in bilayer structures. The formation of such tightly packed lipid rafts is important for different signal transduction pathways, through the regulation of membrane-associating proteins, that can justify several pharmacological activities of this compound.

  6. Temperature-Sensitive Pleiotropic Revertants from a Mutant in the AROM Gene Cluster of NEUROSPORA CRASSA

    PubMed Central

    Case, Mary E.; Giles, Norman H.

    1974-01-01

    Genetical and biochemical studies have been performed with revertants induced in a polyaromatic mutant (No. 58) in the arom gene cluster of Neurospora crassa. In addition to complete and partial revertants able to grow on minimal at both 25° and 35°, temperature-sensitive revertants capable of growth on minimal at 25° but not at 35° have been recovered. One of these revertants has been shown to lack biosynthetic dehydroquinase activity at both temperatures (utilizing the inducible catabolic isozyme for growth at 25°), to have dehydroshikimate reductase activity only at 25°, and to form an arom aggregate having a molecular weight approximately one-half that of wild type. These results are interpreted as indicating that pleiotropic mutants in the arom gene cluster can result from missense mutations, as well as from nonsense mutations as indicated in previous studies. PMID:4365170

  7. Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

    PubMed Central

    Pereira, Thiago Melo Costa; Pimenta, Fabio Silva; Porto, Marcella Lima; Baldo, Marcelo Perim; Campagnaro, Bianca Prandi; Gava, Agata Lages; Meyrelles, Silvana Santos; Vasquez, Elisardo Corral

    2016-01-01

    Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin), cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation. In the near future, experimental studies are expected to clear the intracellular pathways involving coadjuvants. The design of clinical trials may also contribute to new strategies with coadjuvants against the harmful effects of diabetic complications. PMID:27527163

  8. Pleiotropic effects of transforming growth factor-β in hematopoietic stem-cell transplantation.

    PubMed

    Coomes, Stephanie M; Moore, Bethany B

    2010-12-15

    Transforming growth factor (TGF)-β is a pleiotropic cytokine with beneficial and detrimental effects posthematopoietic stem-cell transplantation. TGF-β is increased in specific sites postengraftment and can suppress immune responses and maintain peripheral tolerance. Thus, TGF-β may promote allograft acceptance. However, TGF-β is also the central pathogenic cytokine in fibrotic disease and likely promotes pneumonitis. Although TGF-β can enhance leukocyte recruitment and IgA production, it inhibits both innate and adaptive immune cell function and antiviral host defense posthematopoietic stem-cell transplantation. This review will focus on the current understanding of TGF-β biology and the numerous ways it can impact outcomes posttransplant.

  9. Function of the Neuropilin Family as Essential Pleiotropic Cell Surface Receptors†

    PubMed Central

    Parker, Matthew W.; Guo, Hou-Fu; Li, Xiaobo; Linkugel, Andrew D.; Vander Kooi, Craig W.

    2012-01-01

    The neuropilin (Nrp) family are essential multifunctional vertebrate cell surface receptors. Nrps were initially characterized as receptors for class III Semaphorin (Sema3) family members, functioning in axon guidance. Nrps have also been shown to be critical for Vascular Endothelial Growth Factor (VEGF) dependent angiogenesis. Intriguingly, recent data show that Nrp function in these seemingly divergent pathways is critically determined by ligand-mediated cross-talk, which underlies Nrp function in both physiological and pathological processes. In addition to functioning in these two pathways, Nrps have been shown to specifically function in a number of other fundamental signaling pathways as well. Multiple general mechanisms have been found to directly contribute to the pleiotropic function of Nrp. Here we review critical general features of Nrps function as essential receptors integrating multiple molecular cues into diverse cellular signaling. PMID:23116416

  10. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations.

    PubMed

    Wilkie, Andrew O M

    2005-04-01

    The discovery in 1994 that highly specific mutations of fibroblast growth factor (FGF) receptor 3 caused the most common form of human short-limbed dwarfism, achondroplasia, heralded a new era in FGF receptor (FGFR) biology. A decade later, the purpose of this review is to survey how the study of humans with FGFR mutations continues to provide insights into FGFR function in health and disease, and the clinical applications of these findings. Amongst the most interesting recent discoveries have been the description of novel phenotypes associated with FGFR1 and FGFR3 mutations; identification of fundamental differences in the cellular mechanisms of mutant FGFR2 and FGFR3 action; and the direct identification of FGFR2 and FGFR3 mutations in sperm. These clinical observations illustrate the pleiotropism of FGFR action and fuel ongoing efforts to understand the rich biology and pathophysiology of the FGF signalling system.

  11. Does a pleiotropic gene explain deafness and blue irises in white cats?

    PubMed

    Geigy, Caroline A; Heid, Silvia; Steffen, Frank; Danielson, Kristen; Jaggy, André; Gaillard, Claude

    2007-05-01

    The prevalence of deafness is high in cat populations in which the dominant white gene is segregating. The objective of this study was to investigate whether there is a gene that is responsible for deafness as well as for blue eyes and to establish a plausible mode of inheritance. For this purpose, data from an experimental colony with deaf cats were analyzed. The hearing status was determined by acoustically evoked brain stem responses (BAER). Complex segregation analyses were conducted to find out the most probable mode of inheritance using maximum likelihood procedures. The prevalence of deafness and partial hearing in the experimental colony was 67% and 29%, respectively. The results of the bivariate segregation analysis support the hypothesis of a pleiotropic major gene segregating for deafness and blue iris colour. The high heritability coefficients for both traits, 0.55 and 0.75 respectively, indicate that beside the major gene there is an important influence of polygenic effects.

  12. Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.

    PubMed

    Luthra, Pratibha Mehta; Lal, Neetika

    2016-02-15

    GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM.

  13. Regulatory Physiology

    NASA Technical Reports Server (NTRS)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  14. Regulatory Anatomy

    PubMed Central

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape. PMID:26139952

  15. Pleiotropic effects on subclasses of HDL, adiposity, and glucose metabolism in adult Alaskan Eskimos.

    PubMed

    Tejero, M Elizabeth; Voruganti, V S; Cai, Guowen; Cole, Shelley A; Laston, Sandra; Wenger, Charlotte R; Mac Cluer, Jean W; Dyke, Bennet; Devereux, Richard; Ebbesson, Sven O; Fabsitz, Richard R; Howard, B V; Comuzzie, A G

    2010-01-01

    The aim of this study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high-density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity, and glucose metabolism in adult Alaskan Eskimos. The present family study included 1,214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds, and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for the isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total, and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 +/- 0.11 for LDL(2) (intermediate) and 0.89 +/- 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate, and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions, HDL size and measures of adiposity, and LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity, and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity, and glucose regulation.

  16. Pleiotropic effects on subclasses of HDL, adiposity and glucose metabolism in adult Alaskan Eskimos

    PubMed Central

    Tejero, ME; Voruganti, VS; Cai, G; Cole, SA; Laston, S; Wenger, CR; MacCluer, JW; Dyke, B; Devereux, R; Ebbesson, SO; Fabsitz, RR; Howard, BV; Comuzzie, AG

    2012-01-01

    The aim of the present study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity and glucose metabolism in adult Alaskan Eskimos. The present family study included 1214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 ± 0.11 for LDL2 (intermediate) to 0.89 ± 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions and HDL size and measures of adiposity, LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity and glucose regulation. PMID:19950191

  17. Classical and pleiotropic actions of dipyridamole: Not enough light to illuminate the dark tunnel?

    PubMed

    Balakumar, Pitchai; Nyo, Ying Hui; Renushia, Raja; Raaginey, Devarajan; Oh, Ann Nah; Varatharajan, Rajavel; Dhanaraj, Sokkalingam A

    2014-09-01

    Dipyridamole is a platelet inhibitor indicated for the secondary prevention of transient ischemic attack. It inhibits the enzyme phosphodiesterase, elevates cAMP and cGMP levels and prevents platelet aggregation. Dipyridamole inhibits the cellular uptake of adenosine into red blood cells, platelets and endothelial cells that results in increased extracellular availability of adenosine, leading to modulation of cardiovascular function. The antiplatelet action of dipyridamole might offer therapeutic benefits in secondary stroke prevention in combination with aspirin. Inflammation and oxidative stress play an important role in atherosclerosis and thrombosis development, leading to stroke progression. Studies demonstrated anti-inflammatory, anti-oxidant and anti-proliferative actions of dipyridamole. These pleiotropic potentials of dipyridamole might contribute to improved therapeutic outcomes when used with aspirin in preventing secondary stroke. Dipyridamole was documented as a coronary vasodilator 5 decades ago. The therapeutic failure of dipyridamole as a coronary vasodilator is linked with induction of 'coronary steal' phenomenon in which by dilating resistance vessels in non-ischemic zone, dipyridamole diverts the already reduced blood flow away from the area of ischemic myocardium. Dipyridamole at high-dose could cause a marked 'coronary steal' effect. Dipyridamole, however, at low-dose could have a minimal hemodynamic effect. Low-dose dipyridamole treatment has a therapeutic potential in partially preventing diabetes mellitus-induced experimental vascular endothelial and renal abnormalities by enhancing endothelial nitric oxide signals and inducing renovascular reduction of oxidative stress. In spite of plenteous research on dipyridamole's use in clinics, its precise clinical application is still obscure. This review sheds lights on pleiotropic pharmacological actions and therapeutic potentials of dipyridamole.

  18. Clinical implications of cardiovascular preventing pleiotropic effects of dipeptidyl peptidase-4 inhibitors.

    PubMed

    Chrysant, Steven G; Chrysant, George S

    2012-06-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP-4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose-lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Leveraging electronic health records to study pleiotropic effects on bipolar disorder and medical comorbidities

    PubMed Central

    Prieto, M L; Ryu, E; Jenkins, G D; Batzler, A; Nassan, M M; Cuellar-Barboza, A B; Pathak, J; McElroy, S L; Frye, M A; Biernacka, J M

    2016-01-01

    Patients with bipolar disorder (BD) have a high prevalence of comorbid medical illness. However, the mechanisms underlying these comorbidities with BD are not well known. Certain genetic variants may have pleiotropic effects, increasing the risk of BD and other medical illnesses simultaneously. In this study, we evaluated the association of BD-susceptibility genetic variants with various medical conditions that tend to co-exist with BD, using electronic health records (EHR) data linked to genome-wide single-nucleotide polymorphism (SNP) data. Data from 7316 Caucasian subjects were used to test the association of 19 EHR-derived phenotypes with 34 SNPs that were previously reported to be associated with BD. After Bonferroni multiple testing correction, P<7.7 × 10−5 was considered statistically significant. The top association findings suggested that the BD risk alleles at SNP rs4765913 in CACNA1C gene and rs7042161 in SVEP1 may be associated with increased risk of ‘cardiac dysrhythmias' (odds ratio (OR)=1.1, P=3.4 × 10−3) and ‘essential hypertension' (OR=1.1, P=3.5 × 10−3), respectively. Although these associations are not statistically significant after multiple testing correction, both genes have been previously implicated with cardiovascular phenotypes. Moreover, we present additional evidence supporting these associations, particularly the association of the SVEP1 SNP with hypertension. This study shows the potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions. PMID:27529678

  20. REVIEWMolecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation

    PubMed Central

    Pabreja, K; Mohd, M A; Koole, C; Wootten, D; Furness, S G B

    2014-01-01

    The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide. Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5 PMID:23889512

  1. ALS herbicide resistance mutations in Raphanus raphanistrum: evaluation of pleiotropic effects on vegetative growth and ALS activity.

    PubMed

    Li, Mei; Yu, Qin; Han, Heping; Vila-Aiub, Martin; Powles, Stephen B

    2013-06-01

    Gene mutations that endow herbicide resistance may cause pleiotropic effects on plant ecology and physiology. This paper reports on the effect of a number of known and novel target-site resistance mutations of the ALS gene (Ala-122-Tyr, Pro-197-Ser, Asp-376-Glu or Trp-574-Leu) on vegetative growth traits of the weed Raphanus raphanistrum. The results from a series of experiments have indicated that none of these ALS resistance mutations imposes negative pleiotropic effects on relative growth rate (RGR), photosynthesis and resource-competitive ability in R. raphanistrum plants. The absence of pleiotropic effects on plant growth occurs in spite of increased (Ala-122-Tyr, Pro-197-Ser, Asp-376-Glu) and decreased (Trp-574-Leu) extractable ALS activity. The absence of detrimental pleiotropic effects on plant growth associated with the ALS target-site resistance mutations reported here is a contributing factor in resistance alleles being at relatively high frequencies in ALS-herbicide-unselected R. raphanistrum populations. © 2012 Society of Chemical Industry.

  2. Enhancer scanning to locate regulatory regions in genomic loci

    PubMed Central

    Buckley, Melissa; Gjyshi, Anxhela; Mendoza-Fandiño, Gustavo; Baskin, Rebekah; Carvalho, Renato S.; Carvalho, Marcelo A.; Woods, Nicholas T.; Monteiro, Alvaro N.A.

    2016-01-01

    The present protocol provides a rapid, streamlined and scalable strategy to systematically scan genomic regions for the presence of transcriptional regulatory regions active in a specific cell type. It creates genomic tiles spanning a region of interest that are subsequently cloned by recombination into a luciferase reporter vector containing the Simian Virus 40 promoter. Tiling clones are transfected into specific cell types to test for the presence of transcriptional regulatory regions. The protocol includes testing of different SNP (single nucleotide polymorphism) alleles to determine their effect on regulatory activity. This procedure provides a systematic framework to identify candidate functional SNPs within a locus during functional analysis of genome-wide association studies. This protocol adapts and combines previous well-established molecular biology methods to provide a streamlined strategy, based on automated primer design and recombinational cloning to rapidly go from a genomic locus to a set of candidate functional SNPs in eight weeks. PMID:26658467

  3. Internal locus of control and vocational rehabilitation.

    PubMed

    Selander, John; Marnetoft, Sven-Uno; Asell, Malin; Selander, Ulrika; Millet, Patrick

    2008-01-01

    In previous studies, internal locus of control (ILC) has been pointed out as a key factor for return to work after vocational rehabilitation. The aim of the current study was to gain a deeper understanding of the concept of ILC in a Swedish vocational rehabilitation context. The study was based on data from 347 long-term sick-listed clients collected at the onset of vocational rehabilitation. A first bi-variate analysis showed that ILC was positively associated with physical functioning and general health, and negatively associated with bodily pain. The analysis also showed that women, more than men, reported high internal locus of control. After a second multivariate analysis, only bodily pain remained associated. It is concluded that there exist a strong and negative association between bodily pain and internal locus of control. Clients with severe pain often also suffer from low internal locus of control. This should be kept in mind when providing vocational rehabilitation.

  4. Molecular Identification of the Schwannomatosis Locus

    DTIC Science & Technology

    2005-07-01

    AD Award Number: DAMD17-03-1-0445 TITLE: Molecular Identification of the Schwannomatosis Locus PRINCIPAL INVESTIGATOR: Mia M. MacCollin, M.D...NUMBER Molecular Identification of the Schwannomatosis Locus 5b. GRANT NUMBER DAMD17-03-1-0445 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER...can be found on next page. 15. SUBJECT TERMS schwannomatosis, tumor suppressor gene, NF2, molecular genetics 16. SECURITY CLASSIFICATION OF: 17

  5. Genome-wide analysis of the regulatory function mediated by the small regulatory psm-mec RNA of methicillin-resistant Staphylococcus aureus.

    PubMed

    Cheung, Gordon Y C; Villaruz, Amer E; Joo, Hwang-Soo; Duong, Anthony C; Yeh, Anthony J; Nguyen, Thuan H; Sturdevant, Daniel E; Queck, S Y; Otto, M

    2014-07-01

    Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance.

  6. Effect of locus of control on disordered eating in athletes: the mediational role of self-regulation of eating attitudes.

    PubMed

    Scoffier, S; Paquet, Y; d'Arripe-Longueville, F

    2010-08-01

    This study examined the influence of locus of control on disordered eating as mediated by the self-regulation of eating attitudes. The assessment instruments were adapted for athletes as the entire sample of 179 volunteer University students (M(age)=21.12; SD=2.87) were all regularly involved in competition. The results showed that (a) an internal locus of control had a positive influence on the self-regulation of eating attitudes in social interaction contexts; (b) self-regulatory eating attitudes had a negative influence on disordered eating in contexts of negative affect, social interaction, and lack of anticipation of consequences on performance; and (c) an internal locus of control had an influence on disordered eating through the mediation of self-regulatory eating attitudes in social interaction contexts, and an external locus of control attributed to the coach and sports friends had an influence on disordered eating through the mediation of self-regulatory eating attitudes in contexts of negative affect, social interaction and lack of anticipation of consequences on performance. This study, combined with an earlier study from Scoffier, Maïano, and d'Arripe-Longueville (2009) on the antecedents of athletes' eating disorders, suggests the powerful impact of the social environment on the development of disordered eating in athletes.

  7. Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering.

    PubMed

    Pedersen, Terje R

    2010-01-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely effective at reducing low-density lipoprotein (LDL) cholesterol and have been demonstrated to reduce mortality and the risk of major cardiovascular events in a number of large primary and secondary prevention studies. The linear relationship between LDL-cholesterol and cardiovascular risk suggests statins work solely by reducing LDL-cholesterol, and that ancillary properties do not contribute to cardiovascular risk reduction. In recent years, however, a number of additional non-lipid-lowering, or 'pleiotropic', effects of statins have been suggested to contribute to their efficacy in cardiovascular disease. The first data to suggest that statins may have benefits beyond lipid lowering came from the Heart Protection Study, in which simvastatin reduced mortality and morbidity even in patients with 'normal' LDL-cholesterol levels (2.6 mmol/L or 100 mg/dL). It has since been demonstrated, however, that cardiovascular risk remains high at this LDL concentration, but is substantially reduced in those achieving levels below 2.0 mmol/L (77 mg/dL). Evidence for the pleiotropic effects of statins in heart failure comes largely from retrospective and subgroup analyses of large studies. When statin therapy is compared with placebo, or when high-dose statin therapy is compared with low-dose treatment, a lower incidence of heart failure or hospitalization is observed. Despite promising retrospective data, however, two prospective studies of rosuvastatin in the treatment of patients with New York Heart Association class II-IV heart failure showed no impact on the primary endpoint and only one of the studies showed a lower rate of hospitalization favouring rosuvastatin. A number of small studies has shown evidence for mechanisms of action of statins outside of LDL-cholesterol lowering, including improvements in endothelial function, halting or retardation of atheroma development, reduction

  8. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.

    PubMed

    Baala, Lekbir; Audollent, Sophie; Martinovic, Jéléna; Ozilou, Catherine; Babron, Marie-Claude; Sivanandamoorthy, Sivanthiny; Saunier, Sophie; Salomon, Rémi; Gonzales, Marie; Rattenberry, Eleanor; Esculpavit, Chantal; Toutain, Annick; Moraine, Claude; Parent, Philippe; Marcorelles, Pascale; Dauge, Marie-Christine; Roume, Joëlle; Le Merrer, Martine; Meiner, Vardiella; Meir, Karen; Menez, Françoise; Beaufrère, Anne-Marie; Francannet, Christine; Tantau, Julia; Sinico, Martine; Dumez, Yves; MacDonald, Fiona; Munnich, Arnold; Lyonnet, Stanislas; Gubler, Marie-Claire; Génin, Emmanuelle; Johnson, Colin A; Vekemans, Michel; Encha-Razavi, Férechté; Attié-Bitach, Tania

    2007-07-01

    Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1-MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM-resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.

  9. Mutations Affecting Expression of the rosy Locus in Drosophila melanogaster

    PubMed Central

    Lee, Chong Sung; Curtis, Daniel; McCarron, Margaret; Love, Carol; Gray, Mark; Bender, Welcome; Chovnick, Arthur

    1987-01-01

    The rosy locus in Drosophila melanogaster codes for the enzyme xanthine dehydrogenase (XDH). Previous studies defined a "control element" near the 5' end of the gene, where variant sites affected the amount of rosy mRNA and protein produced. We have determined the DNA sequence of this region from both genomic and cDNA clones, and from the ry+10 underproducer strain. This variant strain had many sequence differences, so that the site of the regulatory change could not be fixed. A mutagenesis was also undertaken to isolate new regulatory mutations. We induced 376 new mutations with 1-ethyl-1-nitrosourea (ENU) and screened them to isolate those that reduced the amount of XDH protein produced, but did not change the properties of the enzyme. Genetic mapping was used to find mutations located near the 5' end of the gene. DNA from each of seven mutants was cloned and sequenced through the 5' region. Mutant base changes were identified in all seven; they appear to affect splicing and translation of the rosy mRNA. In a related study (T. P. Keith et al. 1987), the genomic and cDNA sequences are extended through the 3' end of the gene; the combined sequences define the processing pattern of the rosy transcript and predict the amino acid sequence of XDH. PMID:3036645

  10. Multivariate analysis of maize disease resistances suggests a pleiotropic genetic basis and implicates a GST gene

    PubMed Central

    Wisser, Randall J.; Kolkman, Judith M.; Patzoldt, Megan E.; Holland, James B.; Yu, Jianming; Krakowsky, Matthew; Nelson, Rebecca J.; Balint-Kurti, Peter J.

    2011-01-01

    Plants are attacked by pathogens representing diverse taxonomic groups, such that genes providing multiple disease resistance (MDR) are expected to be under positive selection pressure. To address the hypothesis that naturally occurring allelic variation conditions MDR, we extended the framework of structured association mapping to allow for the analysis of correlated complex traits and the identification of pleiotropic genes. The multivariate analytical approach used here is directly applicable to any species and set of traits exhibiting correlation. From our analysis of a diverse panel of maize inbred lines, we discovered high positive genetic correlations between resistances to three globally threatening fungal diseases. The maize panel studied exhibits rapidly decaying linkage disequilibrium that generally occurs within 1 or 2 kb, which is less than the average length of a maize gene. The positive correlations therefore suggested that functional allelic variation at specific genes for MDR exists in maize. Using a multivariate test statistic, a glutathione S-transferase (GST) gene was found to be associated with modest levels of resistance to all three diseases. Resequencing analysis pinpointed the association to a histidine (basic amino acid) for aspartic acid (acidic amino acid) substitution in the encoded protein domain that defines GST substrate specificity and biochemical activity. The known functions of GSTs suggested that variability in detoxification pathways underlie natural variation in maize MDR. PMID:21490302

  11. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

    PubMed Central

    Hagner, Patrick R.; Man, Hon-Wah; Fontanillo, Celia; Wang, Maria; Couto, Suzana; Breider, Mike; Bjorklund, Chad; Havens, Courtney G.; Lu, Gang; Rychak, Emily; Raymon, Heather; Narla, Rama Krishna; Barnes, Leo; Khambatta, Gody; Chiu, Hsiling; Kosek, Jolanta; Kang, Jian; Amantangelo, Michael D.; Waldman, Michelle; Lopez-Girona, Antonia; Cai, Ti; Pourdehnad, Michael; Trotter, Matthew; Daniel, Thomas O.; Schafer, Peter H.; Klippel, Anke; Thakurta, Anjan; Gandhi, Anita K.

    2015-01-01

    Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA–mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)–stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide. PMID:26002965

  12. Pleiotropic effects of acarbose on atherosclerosis development in rabbits are mediated via upregulating AMPK signals

    PubMed Central

    Chan, Kuei-Chuan; Yu, Meng-Hsun; Lin, Ming-Cheng; Huang, Chien-Ning; Chung, Dai-Jung; Lee, Yi-Ju; Wu, Cheng-Hsun; Wang, Chau-Jong

    2016-01-01

    Acarbose, an α-glucosidase inhibitor, is reported to reduce the incidence of silent myocardial infarction and slow the progression of intima-media thickening in patients with glucose intolerance. Here we investigate other impacts of acarbose on atherosclerosis development and the underlying mechanisms of atherosclerosis initiation and progression in vivo and in vitro. Rabbits fed a high cholesterol diet (HCD) were treated with acarbose (2.5–5.0 mg kg−1). Immunohistochemistry was used to assess the expression of inducible nitric oxide synthase (iNOS), Ras, proliferating cell nuclear antigen (PCNA), IL-6, β-galactosidase, and p-AMPK in atherosclerotic lesions. Treatment with acarbose in HCD-fed rabbits was found to significantly reduce the severity of aortic atheroma and neointimal expression of α-actin, PCNA, IL-6, TNF-α, Ras, and β-galactosidase; to significantly increase expression of iNOS and p-AMPK, but not to affect serum levels of glucose, total cholesterol, and LDL. Western blot analysis showed acarbose dose-dependently decreased β-galactosidase and Ras expression and increased p-AMPK expression in TNF-α-treated A7r5 cells. In addition, acarbose restored p-AMPK and iNOS levels in AMPK inhibitor- and iNOS inhibitor-treated A7r5 cells, respectively. In conclusion, acarbose can pleiotropically inhibit rabbit atherosclerosis by reducing inflammation, senescence, and VSMCs proliferation/migration via upregulating AMPK signals. PMID:27924924

  13. Pleiotropic QTL on chromosome 19q13 for triglycerides and adiposity: the HERITAGE Family Study.

    PubMed

    Feitosa, Mary F; Rice, Treva; North, Kari E; Kraja, Aldi; Rankinen, Tuomo; Leon, Arthur S; Skinner, James S; Blangero, John; Bouchard, Claude; Rao, D C

    2006-04-01

    Motivated by strong correlations between plasma levels of triglycerides (TG) and adiposity traits, we conducted a series of bivariate genome-wide linkage analyses of TG with body mass index (BMI), total fat mass (FAT), percentage of body fat (FATPC), and abdominal subcutaneous fat (ASF). Maximum lod scores of 3.3, 3.0, 2.2 and 2.4, respectively, were found on chromosome 19q13. This linkage region includes the APOE gene, a predictor of variation in lipid-lipoprotein levels, and the hormone-sensitive lipase (LIPE) gene, a key enzyme in the mobilization of fatty acids from triglyceride stores. In addition, the adiposity measures together with the APOE marker showed significant association with TG levels (p = 0.02 to p = 0.03). In summary, these results suggest that one or more QTLs in the 19q13 region jointly influence TG levels and adiposity. Polymorphisms in the APOE gene, and possibly LIPE gene, appear to be strong candidates for the source of this pleiotropic QTL.

  14. A cysG mutant strain of Rhizobium etli pleiotropically defective in sulfate and nitrate assimilation.

    PubMed Central

    Tate, R; Riccio, A; Iaccarino, M; Patriarca, E J

    1997-01-01

    By its inability to grow on sulfate as the sole sulfur source, a mutant strain (CTNUX8) of Rhizobium etli carrying Tn5 was isolated and characterized. Sequence analysis showed that Tn5 is inserted into a cysG (siroheme synthetase)-homologous gene. By RNase protection assays, it was established that the cysG-like gene had a basal level of expression in thiosulfate- or cysteine-grown cells, which was induced when sulfate or methionine was used. Unlike its wild-type parent (strain CE3), the mutant strain, CTNUX8, was also unable to grow on nitrate as the sole nitrogen source and was unable to induce a high level of nitrite reductase. Despite its pleiotropic phenotype, strain CTNUX8 was able to induce pink, effective (N2-fixing) nodules on the roots of Phaseolus vulgaris plants. However, mixed inoculation experiments showed that strain CTNUX8 is significantly different from the wild type in its ability to nodulate. Our data support the notion that sulfate (or sulfite) is the sulfur source of R. etli in the rhizosphere, while cysteine, methionine, or glutathione is supplied by the root cells to bacteria growing inside the plant. PMID:9393698

  15. Pleiotropic function of TRPV4 ion channels in the central nervous system.

    PubMed

    Kanju, Patrick; Liedtke, Wolfgang

    2016-12-01

    What is the topic of this review? In this concise review, we highlight insights into the role of transient receptor potential, vanilloid type 4 (TRPV4) ion channels in the CNS, results that have been contributed over the last 16 years since the initial discovery of the channel. What advances does it highlight? TRPV4 has been found to function in neurons, astroglia and microglia, both in physiological (e.g. astrocytic neurovascular coupling, neuronal membrane potential at physiological temperature) and in pathological conditions (e.g. mechanical trauma), so far recorded as exciting findings in need of more in-depth mechanistic clarification. Transient receptor potential, vanilloid type 4 (TRPV4) ion channels are osmo-mechano-TRP channels, with pleiotropic function and expression in many different types of tissues and cells. They have also been found to be involved in pain and inflammation. Studies have focused on the role of TRPV4 in peripheral sensory neurons, but its expression and function in central nervous glial cells and neurons has also been documented. In this overview, based on the senior author's (WL) lecture at the recent recent joint meeting of APS/The Physiological Society in Dublin, we concisely review evidence of TRPV4 expression and function in the CNS and how TRPV4 function can be modulated for therapeutic benefit of neuropsychiatric disorders. Novel TRPV4-inhibitory compounds developed recently in the authors' laboratory are also discussed. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

  16. Genetics of human body size and shape: pleiotropic and independent genetic determinants of adiposity.

    PubMed

    Livshits, G; Yakovenko, K; Ginsburg, E; Kobyliansky, E

    1998-01-01

    The present study utilized pedigree data from three ethnically different populations of Kirghizstan, Turkmenia and Chuvasha. Principal component analysis was performed on a matrix of genetic correlations between 22 measures of adiposity, including skinfolds, circumferences and indices. Findings are summarized as follows: (1) All three genetic matrices were not positive definite and the first four factors retained even after exclusion RG > or = 1.0, explained from 88% to 97% of the total additive genetic variation in the 22 trials studied. This clearly emphasizes the massive involvement of pleiotropic gene effects in the variability of adiposity traits. (2) Despite the quite natural differences in pairwise correlations between the adiposity traits in the three ethnically different samples under study, factor analysis revealed a common basic pattern of covariability for the adiposity traits. In each of the three samples, four genetic factors were retained, namely, the amount of subcutaneous fat, the total body obesity, the pattern of distribution of subcutaneous fat and the central adiposity distribution. (3) Genetic correlations between the retained four factors were virtually non-existent, suggesting that several independent genetic sources may be governing the variation of adiposity traits. (4) Variance decomposition analysis on the obtained genetic factors leaves no doubt regarding the substantial familial and (most probably genetic) effects on variation of each factor in each studied population. The similarity of results in the three different samples indicates that the findings may be deemed valid and reliable descriptions of the genetic variation and covariation pattern of adiposity traits in the human species.

  17. An update on the cardiovascular pleiotropic effects of milk and milk products.

    PubMed

    Chrysant, Steven G; Chrysant, George S

    2013-07-01

    Hypertension is a major risk factor in addition to atherosclerosis and type 2 diabetes mellitus for the development of coronary heart disease and strokes. Several prospective clinical studies have demonstrated a possible protective effect of milk and dairy product consumption on these conditions. The putative effects of milk and dairy products are possibly mediated through their mineral content of calcium, magnesium, potassium, and vitamin D. These dairy substances exercise their blood pressure-lowering effect either directly on the arterial wall by these minerals or indirectly through blockade of the angiotensin-converting enzyme (ACE) by the amino acids contained in the casein and whey of milk. The blockade of ACE results in the inhibition of production of angiotensin II, a potent vasoconstrictive peptide, and the prevention of degradation of bradykinin, a potent vasodilating peptide. For this concise review, a Medline search of the English language literature was conducted from 2006 to September 2012 and 16 pertinent papers were selected. The potential beneficial pleiotropic effects from these studies together with collateral literature will be discussed in this review. © 2013 Wiley Periodicals, Inc.

  18. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL.

    PubMed

    Hagner, Patrick R; Man, Hon-Wah; Fontanillo, Celia; Wang, Maria; Couto, Suzana; Breider, Mike; Bjorklund, Chad; Havens, Courtney G; Lu, Gang; Rychak, Emily; Raymon, Heather; Narla, Rama Krishna; Barnes, Leo; Khambatta, Gody; Chiu, Hsiling; Kosek, Jolanta; Kang, Jian; Amantangelo, Michael D; Waldman, Michelle; Lopez-Girona, Antonia; Cai, Ti; Pourdehnad, Michael; Trotter, Matthew; Daniel, Thomas O; Schafer, Peter H; Klippel, Anke; Thakurta, Anjan; Chopra, Rajesh; Gandhi, Anita K

    2015-08-06

    Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.

  19. Cytoplasmic male sterility in Mimulus hybrids has pleiotropic effects on corolla and pistil traits.

    PubMed

    Barr, C M; Fishman, L

    2011-05-01

    The mechanisms underlying genetic associations have important consequences for evolutionary outcomes, but distinguishing linkage from pleiotropy is often difficult. Here, we use a fine mapping approach to determine the genetic basis of association between cytonuclear male sterility and other floral traits in Mimulus hybrids. Previous work has shown that male sterility in hybrids between Mimulus guttatus and Mimulus nasutus is due to interactions between a mitochondrial gene from M. guttatus and two tightly linked nuclear restorer alleles on Linkage Group 7, and that male sterility is associated with reduced corolla size. In the present study, we generated a set of nearly isogenic lines segregating for the restorer region and male sterility, but with unique flanking introgressions. Male-sterile flowers had significantly smaller corollas, longer styles and greater stigmatic exsertion than fertile flowers. Because these effects were significant regardless of the genotypic composition of introgressions flanking the restorer region, they suggest that these floral differences are a direct byproduct of the genetic incompatibility causing anther abortion. In addition, we found a non-significant but intriguing trend for male-sterile plants to produce more seeds per flower than fertile siblings after supplemental pollination. Such pleiotropic effects may underlie the corolla dimorphism frequently observed in gynodioecious taxa and may affect selection on cytoplasmic male sterility genes when they initially arise.

  20. Cytoplasmic male sterility in Mimulus hybrids has pleiotropic effects on corolla and pistil traits

    PubMed Central

    Barr, C M; Fishman, L

    2011-01-01

    The mechanisms underlying genetic associations have important consequences for evolutionary outcomes, but distinguishing linkage from pleiotropy is often difficult. Here, we use a fine mapping approach to determine the genetic basis of association between cytonuclear male sterility and other floral traits in Mimulus hybrids. Previous work has shown that male sterility in hybrids between Mimulus guttatus and Mimulus nasutus is due to interactions between a mitochondrial gene from M. guttatus and two tightly linked nuclear restorer alleles on Linkage Group 7, and that male sterility is associated with reduced corolla size. In the present study, we generated a set of nearly isogenic lines segregating for the restorer region and male sterility, but with unique flanking introgressions. Male-sterile flowers had significantly smaller corollas, longer styles and greater stigmatic exsertion than fertile flowers. Because these effects were significant regardless of the genotypic composition of introgressions flanking the restorer region, they suggest that these floral differences are a direct byproduct of the genetic incompatibility causing anther abortion. In addition, we found a non-significant but intriguing trend for male-sterile plants to produce more seeds per flower than fertile siblings after supplemental pollination. Such pleiotropic effects may underlie the corolla dimorphism frequently observed in gynodioecious taxa and may affect selection on cytoplasmic male sterility genes when they initially arise. PMID:21245895

  1. Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia

    PubMed Central

    Weng, Ching-Hui; Chung, Fa-Po; Chen, Yao-Chang; Lin, Shien-Fong; Huang, Po-Hsun; Kuo, Terry B. J.; Hsu, Wei-Hsuan; Su, Wen-Cheng; Sung, Yen-Ling; Lin, Yenn-Jiang; Chang, Shih-Lin; Lo, Li-Wei; Yeh, Hung-I; Chen, Yi-Jen; Hong, Yi-Ren; Chen, Shih-Ann; Hu, Yu-Feng

    2016-01-01

    Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage. PMID:27966586

  2. Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease.

    PubMed

    Steven, Sebastian; Münzel, Thomas; Daiber, Andreas

    2015-08-05

    Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease.

  3. STATINS MORE THAN CHOLESTEROL LOWERING AGENTS IN ALZHEIMER DISEASE: THEIR PLEIOTROPIC FUNCTIONS AS POTENTIAL THERAPEUTIC TARGETS

    PubMed Central

    Barone, Eugenio; Domenico, Fabio Di; Butterfield, D. Allan

    2013-01-01

    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative ad nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. PMID:24231510

  4. Metformin Beyond Diabetes: Pleiotropic Benefits of Metformin in Attenuation of Atherosclerosis

    PubMed Central

    Forouzandeh, Farshad; Salazar, Gloria; Patrushev, Nikolay; Xiong, Shiqin; Hilenski, Lula; Fei, Baowei; Alexander, R. Wayne

    2014-01-01

    Background Clinical studies show that metformin attenuates all‐cause mortality and myocardial infarction compared with other medications for type 2 diabetes, even at similar glycemic levels. However, there is paucity of data in the euglycemic state on the vasculoprotective effects of metformin. The objectives of this study are to evaluate the effects of metformin on ameliorating atherosclerosis. Methods and Results Using ApoE−/− C57BL/6J mice, we found that metformin attenuates atherosclerosis and vascular senescence in mice fed a high‐fat diet and prevents the upregulation of angiotensin II type 1 receptor by a high‐fat diet in the aortas of mice. Thus, considering the known deleterious effects of angiotensin II mediated by angiotensin II type 1 receptor, the vascular benefits of metformin may be mediated, at least in part, by angiotensin II type 1 receptor downregulation. Moreover, we found that metformin can cause weight loss without hypoglycemia. We also found that metformin increases the antioxidant superoxide dismutase‐1. Conclusion Pleiotropic effects of metformin ameliorate atherosclerosis and vascular senescence. PMID:25527624

  5. Uncoupling the Pleiotropic Phenotypes of clk-1 with tRNA Missense Suppressors in Caenorhabditis elegans

    PubMed Central

    Branicky, Robyn; Nguyen, Phuong Anh Thi; Hekimi, Siegfried

    2006-01-01

    clk-1 encodes a demethoxyubiquinone (DMQ) hydroxylase that is necessary for ubiquinone biosynthesis. When Caenorhabditis elegans clk-1 mutants are grown on bacteria that synthesize ubiquinone (UQ), they are viable but have a pleiotropic phenotype that includes slowed development, behaviors, and aging. However, when grown on UQ-deficient bacteria, the mutants arrest development transiently before growing up to become sterile adults. We identified nine suppressors of the missense mutation clk-1(e2519), which harbors a Glu-to-Lys substitution. All suppress the mutant phenotypes on both UQ-replete and UQ-deficient bacteria. However, each mutant suppresses a different subset of phenotypes, indicating that most phenotypes can be uncoupled from each other. In addition, all suppressors restore the ability to synthesize exceedingly small amounts of UQ, although they still accumulate the precursor DMQ, suggesting that the presence of DMQ is not responsible for the Clk-1 phenotypes. We cloned six of the suppressors, and all encode tRNAGlu genes whose anticodons are altered to read the substituted Lys codon of clk-1(e2519). To our knowledge, these suppressors represent the first missense suppressors identified in any metazoan. The pattern of suppression we observe suggests that the individual members of the tRNAGlu family are expressed in different tissues and at different levels. PMID:16648490

  6. Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease

    PubMed Central

    Steven, Sebastian; Münzel, Thomas; Daiber, Andreas

    2015-01-01

    Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease. PMID:26251902

  7. Pleiotropic effects of insulin and GLP-1 receptor agonists: Potential benefits of the association.

    PubMed

    Cariou, B

    2015-12-01

    The combination of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is an emerging option for patients with type 2 diabetes (T2D). GLP-1RAs have been shown to improve glycaemic control with a low risk of hypoglycaemia and to promote body weight loss. However, GLP-1 receptors (GLP-1Rs) are widely expressed in extrapancreatic tissues and could sustain pleiotropic actions of GLP-1RAs beyond glycaemic control. The underlying molecular mechanisms maintaining these extrapancreatic actions of GLP-1 are complex, and involve GLP-1R signalling in both the brain and several peripheral tissues. The present review focuses specifically on the role of GLP-1RAs in the cardiovascular system and liver. Preclinical data in rodents and pilot studies in humans suggest that GLP-1RAs may have potential beneficial effects on heart function, blood pressure, postprandial lipaemia, liver steatosis and non-alcoholic steatohepatitis (NASH). Long-term studies are now warranted to determine the safety and clinical relevance of the association between insulin and GLP-1RAs in T2D.

  8. Pleiotropic relationships between cortisol levels and adiposity: The HERITAGE Family Study.

    PubMed

    Feitosa, Mary F; Rice, Treva; Rosmond, Roland; Rankinen, Tuomo; Leon, Arthur S; Skinner, James S; Wilmore, Jack H; Bouchard, Claude; Rao, D C

    2002-12-01

    To investigate familial basis for the relationship between cortisol adiposity at baseline and their training responses. Bivariate correlation and segregation analyses were employed between cortisol and several adiposity measures [body mass index, fat mass (FM), fat-free mass, percentage of body fat (% BF), abdominal visceral fat (AVF), abdominal subcutaneous fat (ASF), and abdominal total fat (ATF)] from 99 white families and 105 black families. In both races, significant inverse phenotypic correlations were generally observed between cortisol and adiposity measures at baseline but not for training responses. Significant cross-trait familial correlations were found for cortisol with abdominal fat (ASF, AVF, ATF) and overall body adiposity (FM, % BF) measures at baseline, which accounted for 14% to 20% of the phenotypic variance in whites. The cross-trait correlations were not significant for baseline phenotypes in blacks, perhaps because of the small sample size. A bivariate segregation analysis showed evidence of polygenic pleiotropy for cortisol with both abdominal fat and overall adiposity measures that accounted for 14% to 17% of the phenotypic covariance, but major gene pleiotropy was not suggested in whites. However, when ASF, AVF, and ATF were additionally adjusted for FM, no familial cross-trait correlations or polygenic pleiotropy between cortisol and the abdominal fat measures remained. Evidence was found for polygenic pleiotropy but not for pleiotropic major gene effects between cortisol and overall adiposity in whites. However, the covariation of cortisol with abdominal fat phenotypes is dependent on concomitant polygenic factors for total-body fat.

  9. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets.

    PubMed

    Barone, Eugenio; Di Domenico, Fabio; Butterfield, D Allan

    2014-04-15

    Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative and nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects

    PubMed Central

    Burgess, Stephen; Thompson, Simon G.

    2015-01-01

    A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. PMID:25632051

  11. The Pleiotropic Antibacterial Mechanisms of Ursolic Acid against Methicillin-Resistant Staphylococcus aureus (MRSA).

    PubMed

    Wang, Chao-Min; Jhan, Yun-Lian; Tsai, Shang-Jie; Chou, Chang-Hung

    2016-07-07

    (1) BACKGROUND: Several triterpenoids were found to act synergistically with classes of antibiotic, indicating that plant-derived chemicals have potential to be used as therapeutics to enhance the activity of antibiotics against multidrug-resistant pathogens. However, the mode of action of triterpenoids against bacterial pathogens remains unclear. The objective of this study is to evaluate the interaction between ursolic acid against methicillin-resistant Staphylococcus aureus (MRSA); (2) METHODS: The ability of ursolic acid to damage mammalian and bacterial membranes was examined. The proteomic response of methicillin-resistant S. aureus in ursolic acid treatment was investigated using two-dimensional (2D) proteomic analysis; (3) RESULTS: Ursolic acid caused the loss of staphylococcal membrane integrity without hemolytic activity. The comparison of the protein pattern of ursolic acid-treated and normal MRSA cells revealed that ursolic acid affected a variety of proteins involved in the translation process with translational accuracy, ribonuclease and chaperon subunits, glycolysis and oxidative responses; (4) CONCLUSION: The mode of action of ursolic acid appears to be the influence on the integrity of the bacterial membrane initially, followed by inhibition of protein synthesis and the metabolic pathway. These findings reflect that the pleiotropic effects of ursolic acid against MRSA make it a promising antibacterial agent in pharmaceutical research.

  12. Pleiotropic Control by Testosterone of a Learned Vocal Behavior and Its Underlying Neuroplasticity123

    PubMed Central

    Madison, Farrah N.; Parker, Shannon E.

    2016-01-01

    Abstract Steroid hormones coordinate multiple aspects of behavior and physiology. The same hormone often regulates different aspects of a single behavior and its underlying neuroplasticity. This pleiotropic regulation of behavior and physiology is not well understood. Here, we investigated the orchestration by testosterone (T) of birdsong and its neural substrate, the song control system. Male canaries were castrated and received stereotaxic implants filled with T in select brain areas. Implanting T solely in the medial preoptic nucleus (POM) increased the motivation to sing, but did not enhance aspects of song quality such as acoustic structure and stereotypy. In birds implanted with T solely in HVC (proper name), a key sensorimotor region of the song control system, little or no song was observed, similar to castrates that received no T implants of any sort. However, implanting T in HVC and POM simultaneously rescued all measures of song quality. Song amplitude, though, was still lower than what was observed in birds receiving peripheral T treatment. T in POM enhanced HVC volume bilaterally, likely due to activity-dependent changes resulting from an enhanced song rate. T directly in HVC, without increasing song rate, enhanced HVC volume on the ipsilateral side only. T in HVC enhanced the incorporation and recruitment of new neurons into this nucleus, while singing activity can independently influence the incorporation of new neurons into HVC. These results have broad implications for how steroid hormones integrate across different brain regions to coordinate complex social behaviors. PMID:26835510

  13. Circumvention of pleiotropic drug resistance in subcutaneous tumours in vivo with verapamil and clomipramine.

    PubMed

    Merry, S; Hamilton, T G; Flanigan, P; Freshney, R I; Kaye, S B

    1991-01-01

    The development of pleiotropic drug resistance (PDR) in vivo in solid tumour models suggests that a similar process may occur in the clinic. A subline of the Ridgway osteogenic sarcoma (ROS)--a murine subcutaneously-growing solid tumour--with moderate resistance (1.5 fold) to actinomycin D was selected by repeated suboptimal treatment with this drug in vivo. This subline (ROS/ADX/G2) showed cross-resistance to vincristine (3.5 fold) and etoposide (over 5.1 fold) but not to doxorubicin. The resistance could in all cases be partly or completely overcome by treatment with non-cytotoxic doses of verapamil or clomipramine. Resistance to actinomycin in this model was associated with lower (up to 3.2 fold) drug accumulation into tumours which could be increased (up to 2.8 fold) by treatment with 25 micrograms/g verapamil. These data support clinical trials of the use of membrane-active agents to overcome PDR.

  14. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects.

    PubMed

    Burgess, Stephen; Thompson, Simon G

    2015-02-15

    A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This "multivariable Mendelian randomization" approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.

  15. Pleiotropic consequences of mutations towards antibiotic-hypersensitivity in Serratia marcescens.

    PubMed

    Winkler, U; Heller, K B; Folle, B

    1978-03-01

    Various mutants (oxas) were isolated from Serratia marcescens SM-6 by selecting for hypersensitivity towards oxacillin. All mutants found are highly pleiotropic and able to yield spontaneous revertants which behave like the wild-type. Mutant W 1421 mostly studied shows the following phenotypic properties not found in the wild-type: (1) The growth is hypersensitive to various antibiotics, detergents and dyes which differ remarkably in their chemical structure and antibacterial action-mechanism, (2) the cells can be easily solubilized by 0;05% Sodium-dodecyl-sulfate, (3) the cells allow the adsorption of the rough-mutant specific Salmonella phage 6SR; (4) strong cellular binding of crystal violet, (5) agglutination of the cells in 0.3% auramin solution and (6) reduced formation of red pigment. Strain W 1421 is assumed to be a lipopolysaccharide-defective mutant. The outer membrane of mutant W 1421 analyzed by Sodium-dodecylsulfate-polyacrylamide gel electrophoresis possesses a single protein less than that of the wild-type. Mutant W 1421 is further characterized by its low exolipase activity; exoprotease and exonuclease activities are as in the wild-type. This specific exoenzyme deficiency can be overcome either by backmutation to oxacillin-resistance or by growing mutant W 1421 in a medium supplemented with certain non-metabolizable polysaccharides, e.g. glycogen or pectin B. Both polysaccharides increase the exolipase activity of the wild-type too.

  16. Hypothesis: atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease.

    PubMed

    Novela, Cristina; Hennekens, Charles H

    2004-03-01

    The results of numerous long-term, randomized trials show that statins significantly decrease the risks of myocardial infarction, stroke, and vascular death as well as total mortality. The benefits of statins on cardiovascular disease in patients who are not experiencing acute coronary syndromes generally become apparent only after about 2 years. In contrast, atorvastatin conferred an early clinical benefit in the lipid-lowering arm of the long-term Anglo Scandinavian Cardiac Outcomes Trial as well as early benefit on progression of atherosclerosis in the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial. An unexpected finding at baseline in the prospective Interaction of Atorvastatin and Clopidogrel Study was that patients on atorvastatin had significantly decreased platelet activity compared with either patients on other statins or those taking no statins. Atorvastatin has protective effects against membrane lipid peroxidation at pharmacologic concentrations. These and other considerations contribute to the hypothesis that atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease.

  17. Pleiotropic effects of nicotinic acid: beyond high density lipoprotein cholesterol elevation.

    PubMed

    Florentin, Matilda; Liberopoulos, Evangelos N; Kei, Anastazia; Mikhailidis, Dimitri P; Elisaf, Moses S

    2011-07-01

    Treatment with statins has significantly reduced cardiovascular morbidity and mortality, an effect attributed to both the low-density lipoprotein cholesterol (LDL-C) lowering capacity and the pleiotropic actions of these drugs. However, residual risk remains even after intense LDL-C lowering. Therefore, additional treatment with lipid-lowering drugs which improve other lipid parameters and have favourable non-lipid effects may be of clinical value. The aim of the present article is to review the actions of nicotinic acid and comment on the limitations and possible benefits of this drug in clinical practice. Relevant articles were identified through a Pubmed search up to July 2010. Nicotinic acid (niacin) improves the lipid profile and has been associated with reduction in morbidity and mortality from cardiovascular disease. This favourable outcome may be due to several beneficial actions of this drug, such as antithrombotic, anti-inflammatory and antioxidant. However, its use has been limited due to side effects, especially flushing. A novel formulation with a prostaglandin D2 receptor antagonist (laropiprant) appears to substantially decrease the frequency and intensity of flushing, without affecting the other properties of niacin. Some concerns regarding treatment with nicotinic acid include impaired glucose metabolism and elevations in uric acid and homocysteine levels. Nicotinic acid is a safe supplementary (to statins) lipid lowering agent which may also improve cardiovascular outcomes. Whether its combination with laropiprant will be proved equally effective and more favourable in terms of adverse effects remains to be established by large clinical trials.

  18. Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects.

    PubMed

    Caprio, Massimiliano; Infante, Marco; Calanchini, Matilde; Mammi, Caterina; Fabbri, Andrea

    2017-03-01

    Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.

  19. Drosophila melanogaster Prat, a Purine de Novo Synthesis Gene, Has a Pleiotropic Maternal-Effect Phenotype

    PubMed Central

    Malmanche, Nicolas; Clark, Denise V.

    2004-01-01

    In Drosophila melanogaster, two genes, Prat and Prat2, encode the enzyme, amidophosphoribosyltransferase, that performs the first and limiting step in purine de novo synthesis. Only Prat mRNA is present in the female germline and 0- to 2-hr embryos prior to the onset of zygotic transcription. We studied the maternal-effect phenotype caused by Prat loss-of-function mutations, allowing us to examine the effects of decreased purine de novo synthesis during oogenesis and the early stages of embryonic development. In addition to the purine syndrome previously characterized, we found that Prat mutant adult females have a significantly shorter life span and are conditionally semisterile. The semisterility is associated with a pleiotropic phenotype, including egg chamber defects and later effects on embryonic and larval viability. Embryos show mitotic synchrony and/or nuclear content defects at the syncytial blastoderm stages and segmentation defects at later stages. The semisterility is partially rescued by providing Prat mutant females with an RNA-enriched diet as a source of purines. Our results suggest that purine de novo synthesis is a limiting factor during the processes of cellular or nuclear proliferation that take place during egg chamber and embryonic development. PMID:15611171

  20. QSAR classification of estrogen receptor binders and pre-screening of potential pleiotropic EDCs.

    PubMed

    Li, J; Gramatica, P

    2010-10-01

    Endocrine disrupting chemicals (EDCs) are suspected of posing serious threats to human and wildlife health through a variety of mechanisms, these being mainly receptor-mediated modes of action. It is reported that some EDCs exhibit dual activities as estrogen receptor (ER) and androgen receptor (AR) binders. Indeed, such compounds can affect the normal endocrine system through a dual complex mechanism, so steps should be taken not only to identify them a priori from their chemical structure, but also to prioritize them for experimental tests in order to reduce and even forbid their usage. To date, very few EDCs with dual activities have been identified. The present research uses QSARs, to investigate what, so far, is the largest and most heterogeneous ER binder data set (combined METI and EDKB databases). New predictive classification models were derived using different modelling methods and a consensus approach, and these were used to virtually screen a large AR binder data set after strict validation. As a result, 46 AR antagonists were predicted from their chemical structure to also have potential ER binding activities, i.e. pleiotropic EDCs. In addition, 48 not yet recognized ER binders were in silico identified, which increases the number of potential EDCs that are substances of very high concern (SVHC) in REACH. Thus, the proposed screening models, based only on structure information, have the main aim to prioritize experimental tests for the highlighted compounds with potential estrogenic activities and also to design safer alternatives.

  1. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities.

    PubMed

    Li, Weili; Soave, David; Miller, Melissa R; Keenan, Katherine; Lin, Fan; Gong, Jiafen; Chiang, Theodore; Stephenson, Anne L; Durie, Peter; Rommens, Johanna; Sun, Lei; Strug, Lisa J

    2014-02-01

    The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

  2. Tissue specific CTCF occupancy and boundary function at the human growth hormone locus.

    PubMed

    Tsai, Yu-Cheng; Cooke, Nancy E; Liebhaber, Stephen A

    2014-04-01

    The robust and tissue-specific activation of the human growth hormone (hGH) gene cluster in the pituitary and placenta constitutes an informative model for analysis of gene regulation. The five-gene hGH cluster is regulated by two partially overlapping sets of DNase I hypersensitive sites (HSs) that constitute the pituitary (HSI, II, III and V) and placental (HSIII, IV, and V) locus control regions (LCRs). The single placenta-specific LCR component, HSIV, is located at -30 kb to the cluster. Here we generate a series of hGH/BAC transgenes specifically modified to identify structural features of the hGH locus required for its appropriate placental expression. We find that placental specificity is dependent on the overall multigene configuration of the cluster whereas the distance between the cluster and its LCR impacts the level of placental expression. We further observe that a major function of the placental hGH LCR is to insulate the transgene locus from site-of-integration effects. This insulation activity is linked to placenta-specific occupancy of the chromatin architectural protein, CTCF, at HSIV. These data reveal a remarkable combination of structural configurations and regulatory determinants that must work in concert to insure robust and tightly controlled expression from a complex multigene locus.

  3. Forum domain in Drosophila melanogaster cut locus possesses looped domains inside.

    PubMed

    Tchurikov, N A; Krasnov, A N; Ponomarenko, N A; Golova, Y B; Chernov, B K

    1998-07-01

    We have studied the relationship between chromosomal forum domains and looped domains in the cut locus of Drosophila melanogaster . Forum domains were earlier detected by separation in pulsed-field gels of 50-150 kb chromosomal DNA fragments obtained after spontaneous non-random degradation of chromosomes. We have localized the boundary region where cleavage sites are scattered between two forum domains in the regulatory region of the cut locus. We have sequenced a 13 kb region spanning few kilobases from distal domain, the boundary region and part of the proximal forum domain where several scaffold associated regions (SARs) were observed. We conclude that forum domains and looped domains are physically different types of domains and belong to different levels of organization in eukaryotic chromosomes. The boundary region between the neighboring forum domains in the cut locus possesses the Doc element insertion and a micro-satellite stretch and thus might remind a small island of heterochromatin and correspond to so-called intercalary heterochromatin that is known to be located in the 7B1-2 band where the major part of the cut locus is reside.

  4. Transcriptional analysis of degenerate strain Clostridium beijerinckii DG-8052 reveals a pleiotropic response to CaCO3-associated recovery of solvent production

    PubMed Central

    Jiao, Shengyin; Zhang, Yan; Wan, Caixia; Lv, Jia; Du, Renjia; Zhang, Ruijuan; Han, Bei

    2016-01-01

    Degenerate Clostridium beijerinckii strain (DG-8052) can be partially recovered by supplementing CaCO3 to fermentation media. Genome resequencing of DG-8052 showed no general regulator mutated. This study focused on transcriptional analysis of DG-8052 and its response to CaCO3 treatment via microarray. The expressions of 5168 genes capturing 98.6% of C. beijerinckii NCIMB 8052 genome were examed. The results revealed that with addition of CaCO3 565 and 916 genes were significantly up-regulated, and 704 and 1044 genes significantly down-regulated at acidogenic and solventogenic phase of DG-8052, respectively. These genes are primarily responsible for glycolysis to solvent/acid production (poR, pfo), solventogensis (buk, ctf, aldh, adh, bcd) and sporulation (spo0A, sigE, sigma-70, bofA), cell motility and division (ftsA, ftsK, ftsY, ftsH, ftsE, mreB, mreC, mreD, rodA), and molecular chaperones (grpE, dnaK, dnaJ, hsp20, hsp90), etc. The functions of some altered genes in DG-8052, totalling 5.7% at acidogenisis and 8.0% at sovlentogenisis, remain unknown. The response of the degenerate strain to CaCO3 was suggested significantly pleiotropic. This study reveals the multitude of regulatory function that CaCO3 has in clostridia and provides detailed insights into degeneration mechanisms at gene regulation level. It also enables us to develop effective strategies to prevent strain degeneration in future. PMID:27966599

  5. Unexpectedly high allelic diversity at the KIT locus causing dominant white color in the domestic pig.

    PubMed Central

    Pielberg, G; Olsson, C; Syvänen, A C; Andersson, L

    2002-01-01

    Mutations in KIT encoding the mast/stem cell growth factor receptor (MGF) are responsible for coat color variation in domestic pigs. The dominant white phenotype is caused by two mutations, a gene duplication and a splice mutation in one of the copies leading to skipping of exon 17. Here we applied minisequencing and pyrosequencing for quantitative analysis of the number of copies with the splice form. An unexpectedly high genetic diversity was revealed in white pigs. We found four different KIT alleles in a small sample of eight Large White females used as founder animals in a wild boar intercross. A similar number of KIT alleles was found in commercial populations of white Landrace and Large White pigs. We provide evidence for at least two new KIT alleles in pigs, both with a triplication of the gene. The results imply that KIT alleles with the duplication are genetically unstable and new alleles are most likely generated by unequal crossing over. This study provides an improved method for genotyping the complicated Dominant white/KIT locus in pigs. The results also suggest that some alleles may be associated with negative pleiotropic effects on other traits. PMID:11805065

  6. Effect of the estrogen receptor locus on reproduction and production traits in four commercial pig lines.

    PubMed

    Short, T H; Rothschild, M F; Southwood, O I; McLaren, D G; de Vries, A; van der Steen, H; Eckardt, G R; Tuggle, C K; Helm, J; Vaske, D A; Mileham, A J; Plastow, G S

    1997-12-01

    We investigated the effect of the estrogen receptor (ESR) gene on growth and reproductive traits in four Large White-based commercial pig lines. A total of 9,015 litter records from 4,262 sows genotyped at the ESR locus were analyzed to determine whether ESR influenced total number born (TNB) or number born alive (NBA). Teat number (TN), test ADG, ADFI, feed:gain ratio (F/G), and ultrasonic backfat (BF) were also analyzed to determine effects of ESR. The TNB and NBA were increased per favorable allele of ESR (P < .01) with additive effects of .42 (.31) and .39 (.31) pigs/litter in the first parity (later parities), respectively. Dominance effects were near zero in parity one, but they were .16 and .14 pigs for TNB and NBA, respectively, in later parities (P < .05). A favorable additive pleiotropic effect was detected for BF (P < .001; -.11 mm per copy of the favorable litter size allele). There were no detectable effects on ADG or F/G (P > .10), although ADF was reduced 18 g/d per copy of the favorable litter size allele (P < .05). Average TN was 13.1 for pigs carrying the favorable litter size allele vs 13.2 for noncarriers (P < .05). Marker-assisted selection using ESR is warranted to increase litter size in the Large White-based lines considered here and will be of considerable economic value to pork producers.

  7. Role of CTCF Protein in Regulating FMR1 Locus Transcription

    PubMed Central

    Lanni, Stella; Goracci, Martina; Borrelli, Loredana; Mancano, Giorgia; Chiurazzi, Pietro; Moscato, Umberto; Ferrè, Fabrizio; Helmer-Citterich, Manuela; Tabolacci, Elisabetta; Neri, Giovanni

    2013-01-01

    Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, is caused by epigenetic silencing of the FMR1 gene, through expansion and methylation of a CGG triplet repeat (methylated full mutation). An antisense transcript (FMR1-AS1), starting from both promoter and intron 2 of the FMR1 gene, was demonstrated in transcriptionally active alleles, but not in silent FXS alleles. Moreover, a DNA methylation boundary, which is lost in FXS, was recently identified upstream of the FMR1 gene. Several nuclear proteins bind to this region, like the insulator protein CTCF. Here we demonstrate for the first time that rare unmethylated full mutation (UFM) alleles present the same boundary described in wild type (WT) alleles and that CTCF binds to this region, as well as to the FMR1 gene promoter, exon 1 and intron 2 binding sites. Contrariwise, DNA methylation prevents CTCF binding to FXS alleles. Drug-induced CpGs demethylation does not restore this binding. CTCF knock-down experiments clearly established that CTCF does not act as insulator at the active FMR1 locus, despite the presence of a CGG expansion. CTCF depletion induces heterochromatinic histone configuration of the FMR1 locus and results in reduction of FMR1 transcription, which however is not accompanied by spreading of DNA methylation towards the FMR1 promoter. CTCF depletion is also associated with FMR1-AS1 mRNA reduction. Antisense RNA, like sense transcript, is upregulated in UFM and absent in FXS cells and its splicing is correlated to that of the FMR1-mRNA. We conclude that CTCF has a complex role in regulating FMR1 expression, probably through the organization of chromatin loops between sense/antisense transcriptional regulatory regions, as suggested by bioinformatics analysis. PMID:23874213

  8. Role of CTCF protein in regulating FMR1 locus transcription.

    PubMed

    Lanni, Stella; Goracci, Martina; Borrelli, Loredana; Mancano, Giorgia; Chiurazzi, Pietro; Moscato, Umberto; Ferrè, Fabrizio; Helmer-Citterich, Manuela; Tabolacci, Elisabetta; Neri, Giovanni

    2013-01-01

    Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, is caused by epigenetic silencing of the FMR1 gene, through expansion and methylation of a CGG triplet repeat (methylated full mutation). An antisense transcript (FMR1-AS1), starting from both promoter and intron 2 of the FMR1 gene, was demonstrated in transcriptionally active alleles, but not in silent FXS alleles. Moreover, a DNA methylation boundary, which is lost in FXS, was recently identified upstream of the FMR1 gene. Several nuclear proteins bind to this region, like the insulator protein CTCF. Here we demonstrate for the first time that rare unmethylated full mutation (UFM) alleles present the same boundary described in wild type (WT) alleles and that CTCF binds to this region, as well as to the FMR1 gene promoter, exon 1 and intron 2 binding sites. Contrariwise, DNA methylation prevents CTCF binding to FXS alleles. Drug-induced CpGs demethylation does not restore this binding. CTCF knock-down experiments clearly established that CTCF does not act as insulator at the active FMR1 locus, despite the presence of a CGG expansion. CTCF depletion induces heterochromatinic histone configuration of the FMR1 locus and results in reduction of FMR1 transcription, which however is not accompanied by spreading of DNA methylation towards the FMR1 promoter. CTCF depletion is also associated with FMR1-AS1 mRNA reduction. Antisense RNA, like sense transcript, is upregulated in UFM and absent in FXS cells and its splicing is correlated to that of the FMR1-mRNA. We conclude that CTCF has a complex role in regulating FMR1 expression, probably through the organization of chromatin loops between sense/antisense transcriptional regulatory regions, as suggested by bioinformatics analysis.

  9. Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

    PubMed

    Nelson, John R; True, Wayne S; Le, Viet; Mason, R Preston

    2017-10-09

    Residual cardiovascular (CV) risk persists even in statin-treated patients with optimized low-density lipoprotein cholesterol (LDL-C) levels. Other pathways beyond cholesterol contribute to CV risk and the key to reducing residual risk may be addressing non-cholesterol risk factors through pleiotropic mechanisms. The purpose of this review is to examine the literature relating to the potential role of the omega-3 fatty acid eicosapentaenoic acid (EPA) in reducing residual CV risk. The literature shows that EPA can robustly lower plasma triglyceride (TG) levels without raising LDL-C levels and documents EPA to have a broad range of beneficial effects on the atherosclerotic pathway, including those on lipids, lipoproteins, inflammation, oxidation, phospholipid membranes, and the atherosclerotic plaque itself. Clinical imaging studies have consistently demonstrated that EPA decreases plaque vulnerability and prevents plaque progression. The evidence therefore points to a potential role for EPA to reduce residual CV risk. A large randomized study of statin-treated Japanese patients demonstrated that EPA ethyl ester reduced major coronary events by 19% (P = 0.011). However, while there has been significant benefit demonstrated in this and another Japanese CV outcomes study, the question as to whether EPA can play a role in reducing residual CV risk remains to be addressed in broader populations. The large, global, ongoing, randomized, placebo-controlled REDUCE-IT study of high-risk statin-treated patients with persistent hypertriglyceridemia is currently underway to investigate the potential of icosapent ethyl (high-purity prescription EPA ethyl ester) as an add-on therapy to reduce residual CV risk.

  10. Transcriptional regulation by BglJ–RcsB, a pleiotropic heteromeric activator in Escherichia coli

    PubMed Central

    Salscheider, Silja Lucia; Jahn, Andreas; Schnetz, Karin

    2014-01-01

    The bacterial Rcs phosphorelay signals perturbations of the bacterial cell envelope to its response regulator RcsB, which regulates transcription of multiple loci related to motility, biofilm formation and various stress responses. RcsB is unique, as its set of target loci is modulated by interaction with auxiliary regulators including BglJ. The BglJ–RcsB heteromer is known to activate the HNS repressed leuO and bgl loci independent of RcsB phosphorylation. Here, we show that BglJ–RcsB activates the promoters of 10 additional loci (chiA, molR, sfsB, yecT, yqhG, ygiZ, yidL, ykiA, ynbA and ynjI). Furthermore, we mapped the BglJ–RcsB binding site at seven loci and propose a consensus sequence motif. The data suggest that activation by BglJ–RcsB is DNA phasing dependent at some loci, a feature reminiscent of canonical transcriptional activators, while at other loci BglJ–RcsB activation may be indirect by inhibition of HNS-mediated repression. In addition, we show that BglJ–RcsB activates transcription of bgl synergistically with CRP where it shifts the transcription start by 20 bp from a position typical for class I CRP-dependent promoters to a position typical for class II CRP-dependent promoters. Thus, BglJ–RcsB is a pleiotropic transcriptional activator that coordinates regulation with global regulators including CRP, LeuO and HNS. PMID:24335284

  11. Breaking evolutionary and pleiotropic constraints in mammals: On sloths, manatees and homeotic mutations

    PubMed Central

    2011-01-01

    Background Mammals as a rule have seven cervical vertebrae, except for sloths and manatees. Bateson proposed that the change in the number of cervical vertebrae in sloths is due to homeotic transformations. A recent hypothesis proposes that the number of cervical vertebrae in sloths is unchanged and that instead the derived pattern is due to abnormal primaxial/abaxial patterning. Results We test the detailed predictions derived from both hypotheses for the skeletal patterns in sloths and manatees for both hypotheses. We find strong support for Bateson's homeosis hypothesis. The observed vertebral and rib patterns cannot be explained by changes in primaxial/abaxial patterning. Vertebral patterns in sloths and manatees are similar to those in mice and humans with abnormal numbers of cervical vertebrae: incomplete and asymmetric homeotic transformations are common and associated with skeletal abnormalities. In sloths the homeotic vertebral shift involves a large part of the vertebral column. As such, similarity is greatest with mice mutant for genes upstream of Hox. Conclusions We found no skeletal abnormalities in specimens of sister taxa with a normal number of cervical vertebrae. However, we always found such abnormalities in conspecifics with an abnormal number, as in many of the investigated dugongs. These findings strongly support the hypothesis that the evolutionary constraints on changes of the number of cervical vertebrae in mammals is due to deleterious pleitropic effects. We hypothesize that in sloths and manatees low metabolic and activity rates severely reduce the usual stabilizing selection, allowing the breaking of the pleiotropic constraints. This probably also applies to dugongs, although to a lesser extent. PMID:21548920

  12. Breaking evolutionary and pleiotropic constraints in mammals: On sloths, manatees and homeotic mutations.

    PubMed

    Varela-Lasheras, Irma; Bakker, Alexander J; van der Mije, Steven D; Metz, Johan Aj; van Alphen, Joris; Galis, Frietson

    2011-05-06

    Mammals as a rule have seven cervical vertebrae, except for sloths and manatees. Bateson proposed that the change in the number of cervical vertebrae in sloths is due to homeotic transformations. A recent hypothesis proposes that the number of cervical vertebrae in sloths is unchanged and that instead the derived pattern is due to abnormal primaxial/abaxial patterning. We test the detailed predictions derived from both hypotheses for the skeletal patterns in sloths and manatees for both hypotheses. We find strong support for Bateson's homeosis hypothesis. The observed vertebral and rib patterns cannot be explained by changes in primaxial/abaxial patterning. Vertebral patterns in sloths and manatees are similar to those in mice and humans with abnormal numbers of cervical vertebrae: incomplete and asymmetric homeotic transformations are common and associated with skeletal abnormalities. In sloths the homeotic vertebral shift involves a large part of the vertebral column. As such, similarity is greatest with mice mutant for genes upstream of Hox. We found no skeletal abnormalities in specimens of sister taxa with a normal number of cervical vertebrae. However, we always found such abnormalities in conspecifics with an abnormal number, as in many of the investigated dugongs. These findings strongly support the hypothesis that the evolutionary constraints on changes of the number of cervical vertebrae in mammals is due to deleterious pleitropic effects. We hypothesize that in sloths and manatees low metabolic and activity rates severely reduce the usual stabilizing selection, allowing the breaking of the pleiotropic constraints. This probably also applies to dugongs, although to a lesser extent.

  13. The transcriptional repressor ARR1-SRDX suppresses pleiotropic cytokinin activities in Arabidopsis.

    PubMed

    Heyl, Alexander; Ramireddy, Eswar; Brenner, Wolfram G; Riefler, Michael; Allemeersch, Joke; Schmülling, Thomas

    2008-07-01

    The signal transduction of the phytohormone cytokinin is mediated by a multistep histidine-to-aspartate phosphorelay system. One component of this system are B-type response regulators, transcription factors mediating at least part of the response to cytokinin. In planta functional analysis of this family is hampered by the high level of functional redundancy of its 11 members. We generated a dominant repressor version of the Arabidopsis (Arabidopsis thaliana) response regulator ARR1 (ARR1-SRDX) using chimeric repressor silencing technology in order to study the extent of the contribution of B-type response regulators to cytokinin activities. In a protoplast test system, ARR1-SRDX suppressed ARR6:beta-glucuronidase reporter gene activation by different B-type ARRs. 35S:ARR1-SRDX transgenic Arabidopsis plants showed phenotypic changes reminiscent of plants with a reduced cytokinin status, such as a strongly reduced leaf size, an enhanced root system, and larger seeds. Several bioassays showed that 35S:ARR1-SRDX plants have an increased resistance toward cytokinin. The rapid induction of a large part of the cytokinin response genes was dampened. The transcript levels of more than 500 genes were more than 2.5-fold reduced in 35S:ARR1-SRDX transgenic seedlings, suggesting a broad function of B-type ARRs. Collectively, the suppression of pleiotropic cytokinin activities by a dominant repressor version of a B-type ARR indicates that this protein family is involved in mediating most, if not all, of the cytokinin activities in Arabidopsis. In addition, a role for B-type ARRs in mediating cross talk with other pathways is supported by the resistance of 35S:ARR1-SRDX seeds to phytochrome B-mediated inhibition of germination by far-red light. This study demonstrates the usefulness of chimeric repressor silencing technology to overcome redundancy in transcription factor families for functional studies.

  14. Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2.

    PubMed

    Li, Y; Cai, L; Wang, H; Wu, P; Gu, W; Chen, Y; Hao, H; Tang, K; Yi, P; Liu, M; Miao, S; Ye, D

    2011-09-08

    Cancer cells recruit monocytes, macrophages and other inflammatory cells by producing abundant chemoattractants and growth factors, such as macrophage colony-stimulating factor (M-CSF/CSF-1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), to promote tumor growth and dissemination. An understanding of the mechanisms that target cancer cells and regulate tumor microenvironment is essential in designing anticancer therapies. Here, we showed that serum amyloid-A (SAA) and cathelicidin (LL-37) stimulated M-CSF and MCP-1 expression with or without lipopolysaccharide (LPS) administration; conversely, lipoxin-A(4) (LXA(4)) and annexin-A1 (ANXA1) inhibited LPS-induced M-CSF and MCP-1 production by human (HepG2) and mouse (H22) hepatocellular carcinoma cells (HCCs). The effects of LXA(4), ANXA1, SAA and LL-37 were dependent on the activation of their mutual cell-surface receptor formyl peptide receptor-2 (FPR2) and subsequent ROS-MAPK-NF-kB signalings. Furthermore, our results indicated that LPS switched macrophages into an IL-10(low)IL-12(high) M1 profile, whereas M-CSF+MCP-1 and FPR2 agonists skewed them into M2 (IL-10(high)IL-12(low)). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA(4) and ANXA1 induced monocyte differentiation into M2a+M2c-like cells and showed antitumorigenetic activities, whereas SAA, LL-37 and M-CSF+MCP-1 led to M2b- or M2d-like polarization, which exacerbated HCC invasion in vitro and in vivo, respectively. Our results suggest that FPR2 has an appreciable pleiotropic regulator role in tumor immunoediting.

  15. Pleiotropic effects of the mioC mutation on the physiology of Pseudomonas aeruginosa PAO1.

    PubMed

    Yeom, Jinki; Park, Woojun

    2012-10-01

    Flavodoxin (Fld) is a bacterial electron-transfer protein that possesses flavin mononucleotide as a prosthetic group. In the genomes of the Pseudomonas species, the mioC gene is the sole gene, annotated Fld, but its function remains unclear. In this study, phenotype microarray analysis was performed using the wild-type and mioC mutant of pathogenic Pseudomonas aeruginosa PAO1. Our results showed that the mioC mutant is very resistant to oxidative stress. Different antibiotics and metals worked differently on the sensitivity of the mutant. Other pleiotropic effects of mutation in the mioC gene, such as biofilm formation, aggregation ability, motility and colony morphology, were observed under iron stress conditions. Most of the phenotypic and physiological changes could be recovered in the wild type by complementation. Mutation of the mioC gene also influenced the production of pigments. The mioC mutant and mioC over-expressed complementation cells, over-produced pyocyanin and pyoverdine, respectively. Various secreted chemicals were also changed in the mutant, which was confirmed by (1) H NMR analysis. Interestingly, physiological alterations of the mutant strain were restored by the cell-free supernatant of the wild type. The present study demonstrates that the mioC gene plays an important role in the physiology of P. aeruginosa and might be considered as a suitable drug target candidate in pathogenic P. aeruginosa. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  16. Pleiotropic actions of forskolin result in phosphatidylserine exposure in primary trophoblasts.

    PubMed

    Riddell, Meghan R; Winkler-Lowen, Bonnie; Jiang, Yanyan; Davidge, Sandra T; Guilbert, Larry J

    2013-01-01

    , provide evidence that the common differentiation agent forskolin has previously unappreciated pleiotropic effects on trophoblastic cells.

  17. Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus.

    PubMed

    Defronzo, Ralph A; Mehta, Rucha J; Schnure, Joel J

    2013-04-01

    Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-γ to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on β-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs-especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, β cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having

  18. Estradiol negatively modulates the pleiotropic actions of orphanin FQ/nociceptin at proopiomelanocortin synapses.

    PubMed

    Borgquist, Amanda; Kachani, Malika; Tavitian, Nadia; Sinchak, Kevin; Wagner, Edward J

    2013-01-01

    Orphanin FQ/nociceptin (OFQ/N) inhibits the activity of proopiomelanocortin (POMC) neurons located in the hypothalamic arcuate nucleus (ARH) that regulate female sexual behavior and energy balance. We tested the hypothesis that estradiol modulates the ability of OFQ/N to pre- and postsynaptically decrease the excitability of these cells. To this end, whole-cell patch-clamp recordings were performed in hypothalamic slices prepared from ovariectomized rats, including some that were injected with the retrograde tracer Fluorogold in the medial preoptic nucleus (MPN) to label the POMC neurons regulating sexual receptivity. OFQ/N (1 µM) evoked a robust outward current in ARH neurons from vehicle-treated animals that was blocked by the opioid receptor-like (ORL)1 receptor antagonist UFP-101 (100 nM) and the G protein-gated, inwardly rectifying K⁺ (GIRK-1) channel blocker tertiapin (10 nM). OFQ/N also produced a decrease in the frequency of glutamatergic, miniature excitatory postsynaptic currents (mEPSCs), which was also antagonized by UFP-101. Estradiol benzoate (2 µg) increased basal mEPSC frequency and markedly diminished both the OFQ/N-induced activation of postsynaptic GIRK-1 channel currents and the presynaptic inhibition of glutamatergic neurotransmission. These effects were observed in identified POMC neurons, including eight that projected to the MPN. Taken together, these data reveal that estradiol attenuates the pleiotropic inhibitory actions of OFQ/N on POMC neurons: presynaptically through reducing the OFQ/N inhibition of glutamate release and postsynaptically by reducing ORL1 signaling through GIRK channels. As such, they impart critical insight into a mechanism for estradiol to increase the activity of POMC neurons that inhibit sexual receptivity.

  19. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan.

    PubMed

    Ashpole, Nicole M; Logan, Sreemathi; Yabluchanskiy, Andriy; Mitschelen, Matthew C; Yan, Han; Farley, Julie A; Hodges, Erik L; Ungvari, Zoltan; Csiszar, Anna; Chen, Sixia; Georgescu, Constantin; Hubbard, Gene B; Ikeno, Yuji; Sonntag, William E

    2017-04-01

    Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf (f/f) C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

  20. Pleiotropic drug-resistance attenuated genomic library improves elucidation of drug mechanisms.

    PubMed

    Coorey, Namal V C; Matthews, James H; Bellows, David S; Atkinson, Paul H

    2015-11-01

    Identifying Saccharomyces cerevisiae genome-wide gene deletion mutants that confer hypersensitivity to a xenobiotic aids the elucidation of its mechanism of action (MoA). However, the biological activities of many xenobiotics are masked by the pleiotropic drug resistance (PDR) network which effluxes xenobiotics that are PDR substrates. The PDR network in S. cerevisiae is almost entirely under the control of two functionally homologous transcription factors Pdr1p and Pdr3p. Herein we report the construction of a PDR-attenuated haploid non-essential DMA (PA-DMA), lacking PDR1 and PDR3, which permits the MoA elucidation of xenobiotics that are PDR substrates at low concentrations. The functionality of four key cellular processes commonly activated in response to xenobiotic stress: oxidative stress response, general stress response, unfolded stress response and calcium signalling pathways were assessed in the absence of PDR1 and PDR3 genes and were found to unaltered, therefore, these key chemogenomic signatures are not lost when using the PA-DMA. Efficacy of the PA-DMA was demonstrated using cycloheximide and latrunculin A at low nanomolar concentrations to attain chemical genetic profiles that were more specific to their known main mechanisms. We also found a two-fold increase in the number of compounds that are bioactive in the pdr1Δpdr3Δ compared to the wild type strain in screening the commercially available LOPAC(1280) library. The PA-DMA should be particularly applicable to mechanism determination of xenobiotics that have limited availability, such as natural products.

  1. Deficiency of huntingtin has pleiotropic effects in the social amoeba Dictyostelium discoideum.

    PubMed

    Myre, Michael A; Lumsden, Amanda L; Thompson, Morgan N; Wasco, Wilma; MacDonald, Marcy E; Gusella, James F

    2011-04-01

    Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of-function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA-resistant cell-cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca(2+) or Mg(2+) but not pulses of cAMP. Although hd(-) cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd(-) cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid

  2. Pleiotropic Effects of a Methyl Donor Diet in a Novel Animal Model

    PubMed Central

    Shorter, Kimberly R.; Anderson, Vanessa; Cakora, Patricia; Owen, Amy; Lo, Keswick; Crossland, Janet; South, April C. H.; Felder, Michael R.; Vrana, Paul B.

    2014-01-01

    Folate and other methyl-donor pathway components are widely supplemented due to their ability to prevent prenatal neural tube defects. Several lines of evidence suggest that these supplements act through epigenetic mechanisms (e.g. altering DNA methylation). Primary among these are the experiments on the mouse viable yellow allele of the agouti locus (Avy). In the Avy allele, an Intracisternal A-particle retroelement has inserted into the genome adjacent to the agouti gene and is preferentially methylated. To further test these effects, we tested the same diet used in the Avy studies on wild-derived Peromyscus maniculatus, a native North American rodent. We collected tissues from neonatal offspring whose parents were fed the high-methyl donor diet as well as controls. In addition, we assayed coat-color of a natural variant (wide-band agouti = ANb) that overexpresses agouti as a phenotypic biomarker. Our data indicate that these dietary components affected agouti protein production, despite the lack of a retroelement at this locus. Surprisingly, the methyl-donor diet was associated with defects (e.g. ovarian cysts, cataracts) and increased mortality. We also assessed the effects of the diet on behavior: We scored animals in open field and social interaction tests. We observed significant increases in female repetitive behaviors. Thus these data add to a growing number of studies that suggest that these ubiquitously added nutrients may be a human health concern. PMID:25121505

  3. Positional cloning of the nude locus: Genetic, physical, and transcription maps of the region and mutations in the mouse and rat

    SciTech Connect

    Segre, J.A.; Lander, E.S. |; Taylor, B.A.

    1995-08-10

    Mutations in the nude locus in mice and rats produce the pleiotropic phenotype of hairlessness and athymia, resulting in severely compromised immune system. To identify the causative gene, we utilized modern tools and techniques of positional cloning. Specifically, spanning the region in which the nude locus resides, we constructed a genetic map of polymorphic markers, a physical map of yeast artificial chromosomes and bacteriophage P1 clones, and a transcription map of genes obtained by direct cDNA selection and exon trapping. We identified seven novel transcripts with similarity to genes from Drosophila, Caenorhabditis elegans, rat or human and three previously identified mouse genes. Based on our transcription mapping results, we present a novel approach to estimate that the nude locus resides in a region approximately threefold enriched for genes. We confirm a recently published report that the nude phenotype is caused by mutations in a gene encoding a novel winged helix or fork head domain transcription factor, whn. We report as well as the mutations in the rat rnu allele and the complete coding sequence of the rat whn mRNA. 42 refs., 4 figs., 1 tab.

  4. Intrahaplotype polymorphism at the Brassica S locus.

    PubMed Central

    Miege, C; Ruffio-Châble, V; Schierup, M H; Cabrillac, D; Dumas, C; Gaude, T; Cock, J M

    2001-01-01

    The S locus receptor kinase and the S locus glycoproteins are encoded by genes located at the S locus, which controls the self-incompatibility response in Brassica. In class II self-incompatibility haplotypes, S locus glycoproteins can be encoded by two different genes, SLGA and SLGB. In this study, we analyzed the sequences of these genes in several independently isolated plants, all of which carry the same S haplotype (S(2)). Two groups of S(2) haplotypes could be distinguished depending on whether SRK was associated with SLGA or SLGB. Surprisingly, SRK alleles from the two groups could be distinguished at the sequence level, suggesting that recombination rarely occurs between haplotypes of the two groups. An analysis of the distribution of polymorphisms along the S domain of SRK showed that hypervariable domains I and II tend to be conserved within haplotypes but to be highly variable between haplotypes. This is consistent with these domains playing a role in the determination of haplotype specificity. PMID:11606555

  5. The Preconscious: Locus for Significant Written Compositions.

    ERIC Educational Resources Information Center

    Alley, Alvin D.

    1979-01-01

    The author suggests that the preconscious is the true locus of significant prose because of its greater amount of freedom to gather, compare, and rearrange ideas, and that the ultimate challenge to teachers of composition is to give freedom to their students' preconscious processes. (KC)

  6. Exercise Adherence and Locus of Control.

    ERIC Educational Resources Information Center

    Geshuri, Yosef; Glahn, Ronald

    In 1990, a study was conducted to investigate the relationship between students' locus of control and the extent to which they participated in a voluntary exercise program. First-time participants in the "Shape Up" program offered at the Porterville College Fitness Center during the summer and fall semesters of 1990 were identified through the…

  7. A suppressor locus for MODY3-diabetes

    PubMed Central

    Garcia-Gonzalez, Miguel A.; Carette, Claire; Bagattin, Alessia; Chiral, Magali; Makinistoglu, Munevver Parla; Garbay, Serge; Prévost, Géraldine; Madaras, Cécile; Hérault, Yann; Leibovici, Michel; Pontoglio, Marco

    2016-01-01

    Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency. PMID:27667715

  8. Dental Outpatients: Health Locus of Control Correlates.

    ERIC Educational Resources Information Center

    Ludenia, Krista; Donham, Greg W.

    1983-01-01

    Examined relationships among specific personality variables, the Multidimensional Health Locus of Control Scales, and criterion-based ratings by staff dentists with dental outpatients (N=101). Found a consistent relationship between the perception that health is maintained by engaging in health-related behaviors and individual difference measures…

  9. Dental Outpatients: Health Locus of Control Correlates.

    ERIC Educational Resources Information Center

    Ludenia, Krista; Donham, Greg W.

    1983-01-01

    Examined relationships among specific personality variables, the Multidimensional Health Locus of Control Scales, and criterion-based ratings by staff dentists with dental outpatients (N=101). Found a consistent relationship between the perception that health is maintained by engaging in health-related behaviors and individual difference measures…

  10. Multidimensionality of Locus of Control in Females.

    ERIC Educational Resources Information Center

    Kearney, Maureen J.; Kearney, James F.

    The Internal-External (I-E) Locus of Control scale (Rotter, 1966) was administered to 185 male and 185 female university students. The resulting scores were factored, producing two factors for males and four for females. The male factors were the generally-accepted "luck" and "powerful others"; for women, however, the "powerful others" dimension…

  11. Locus of Control, Social Class, and Learning.

    ERIC Educational Resources Information Center

    Vasquez, James A.

    The relationship between locus of control, social class, and learning processes were reviewed by analyzing: (1) externality as a function of socioeconomic status, i.e., the lower the status, the greater the degree of externality; (2) the impact of the early home environment on the child's learning and development; (3) classroom and teacher…

  12. Identification and cloning of a regulatory gene for nitrogen assimilation in the cyanobacterium Synechococcus sp. strain PCC 7942.

    PubMed Central

    Vega-Palas, M A; Madueño, F; Herrero, A; Flores, E

    1990-01-01

    Twenty-seven mutants that were unable to assimilate nitrate were isolated from Synechococcus sp. strain PCC 7942. In addition to mutants that lacked nitrate reductase or nitrite reductase, seven pleiotropic mutants impaired in both reductases, glutamine synthetase, and methylammonium transport were also isolated. One of the pleiotropic mutants was complemented by transformation with a cosmid gene bank from wild-type strain PCC 7942. Three complementing cosmids were isolated, and a 3.1-kilobase-pair DNA fragment that was still able to complement the mutant was identified. The regulatory gene that was cloned (ntcA) appeared to be required for full expression of proteins subject to ammonium repression in Synechococcus sp. PMID:1967601

  13. Analysis of HLA-ABC locus-specific transcription in normal tissues.

    PubMed

    García-Ruano, Ana Belén; Méndez, Rosa; Romero, José María; Cabrera, Teresa; Ruiz-Cabello, Francisco; Garrido, Federico

    2010-12-01

    We developed a novel human leukocyte antigen HLA-ABC locus-specific quantitative real-time polymerase chain reaction (PCR) to determine the locus-specific gene expression of HLA-ABC in peripheral blood leukocytes (PBLs, n = 53), colon mucosa (n = 15), and larynx mucosa (n = 15). Laser-assisted tissue microdissection allowed us to study the selected cells without interference from surrounding stroma. We report evidence on the specificity of the technique, describing the HLA-ABC locus-specific gene expression patterns found in the PBLs and two solid tissues studied. PBLs showed a higher gene expression of HLA-B than of HLA-A or HLA-C (p = 4.7 × 10(-10) and p = 1.6 × 10(-6), respectively). In solid tissue, HLA-A and HLA-B gene expressions were similar and HLA-C expression lower. In particular, in larynx mucosa, significant differences were found between HLA-A and HLA-C expressions and between HLA-B and HLA-C expressions (p = 6.5 × 10(-4) and p = 8.1 × 10(-4), respectively). The same differences were observed in colon mucosa, but significance was not reached (p = 0.08 and p = 0.06, respectively). Differences in locus-specific regulation may be related to the control of cytotoxic responses of NK and CD8 positive T cells. Gene expression of HLA-ABC specific locus showed no intra-individual variability, but there was a high inter-individual variability. This may result from differences in the expression of common regulatory factors that control HLA-ABC constitutive expression.

  14. Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins

    PubMed Central

    Indjeian, Vahan B.; Kingman, Garrett A.; Jones, Felicity C.; Guenther, Catherine A.; Grimwood, Jane; Schmutz, Jeremy; Myers, Richard M.; Kingsley, David M.

    2016-01-01

    SUMMARY Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone size differences in sticklebacks maps to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form. PMID:26774823

  15. Professional and Regulatory Search

    EPA Pesticide Factsheets

    Professional and Regulatory search are designed for people who use EPA web resources to do their job. You will be searching collections where information that is not relevant to Environmental and Regulatory professionals.

  16. Constraints on the evolution of a doublesex target gene arising from doublesex’s pleiotropic deployment

    PubMed Central

    Luo, Shengzhan D.; Baker, Bruce S.

    2015-01-01

    Regulatory evolution,” that is, changes in a gene’s expression pattern through changes at its regulatory sequence, rather than changes at the coding sequence of the gene or changes of the upstream transcription factors, has been increasingly recognized as a pervasive evolution mechanism. Many somatic sexually dimorphic features of Drosophila melanogaster are the results of gene expression regulated by the doublesex (dsx) gene, which encodes sex-specific transcription factors (DSXF in females and DSXM in males). Rapid changes in such sexually dimorphic features are likely a result of changes at the regulatory sequence of the target genes. We focused on the Flavin-containing monooxygenase-2 (Fmo-2) gene, a likely direct dsx target, to elucidate how sexually dimorphic expression and its evolution are brought about. We found that dsx is deployed to regulate the Fmo-2 transcription both in the midgut and in fat body cells of the spermatheca (a female-specific tissue), through a canonical DSX-binding site in the Fmo-2 regulatory sequence. In the melanogaster group, Fmo-2 transcription in the midgut has evolved rapidly, in contrast to the conserved spermathecal transcription. We identified two cis-regulatory modules (CRM-p and CRM-d) that direct sexually monomorphic or dimorphic Fmo-2 transcription, respectively, in the midguts of these species. Changes of Fmo-2 transcription in the midgut from sexually dimorphic to sexually monomorphic in some species are caused by the loss of CRM-d function, but not the loss of the canonical DSX-binding site. Thus, conferring transcriptional regulation on a CRM level allows the regulation to evolve rapidly in one tissue while evading evolutionary constraints posed by other tissues. PMID:25675536

  17. Arabidopsis TERMINAL FLOWER 2 gene encodes a heterochromatin protein 1 homolog and represses both FLOWERING LOCUS T to regulate flowering time and several floral homeotic genes.

    PubMed

    Kotake, Toshihisa; Takada, Shinobu; Nakahigashi, Kenji; Ohto, Masaaki; Goto, Koji

    2003-06-01

    Floral transition should be strictly regulated because it is one of the most critical developmental processes in plants. Arabidopsis terminal flower 2 (tfl2) mutants show an early-flowering phenotype that is relatively insensitive to photoperiod, as well as several other pleiotropic phenotypes. We found that the early flowering of tfl2 is caused mainly by ectopic expression of the FLOWERING LOCUS T (FT) gene, a floral pathway integrator. Molecular cloning of TFL2 showed that it encodes a protein with homology to heterochromatin protein 1 (HP1) of animals and Swi6 of fission yeast. TFL2 protein localizes in subnuclear foci and expression of the TFL2 gene complemented yeast swi6(-) mutants. These results suggested that TFL2 might function as an HP1 in Arabidopsis: Gene expression analyses using DNA microarrays, however, did not show an increase in the expression of heterochromatin genes in tfl2 mutants but instead showed the upregulation of the floral homeotic genes APETALA3, PISTILLATA, AGAMOUS and SEPALLATA3. The pleiotropic phenotype of the tfl2 mutant could reflect the fact that TFL2 represses the expression of multiple genes. Our results demonstrate that despite its homology to HP1, TFL2 is involved in the repression of specific euchromatin genes and not heterochromatin genes in Arabidopsis.

  18. The Impact of Locus of Control on Language Achievement

    ERIC Educational Resources Information Center

    Nodoushan, Mohammad Ali Salmani

    2012-01-01

    This study hypothesized that students' loci of control affected their language achievement. 198 (N = 198) EFL students took the Rotter's (1966) locus of control test and were classified as locus-internal (ni = 78), and locus-external (ne = 120). They then took their ordinary courses and at the end of the semester, they were given their exams.…

  19. Cognitive Evaluation Theory, Locus of Control and Positive Verbal Feedback.

    ERIC Educational Resources Information Center

    Lonky, Edward; Reihman, Jacqueline

    This study tests the hypothesis that individual differences in locus of control orientation may mediate elementary school students' responses to positive verbal feedback. A total of 30 kindergarten through fourth grade subjects were assessed for locus of control orientation using the Bialer Children's Locus of Control Questionnaire. To establish a…

  20. Self-Esteem, Locus of Control, and Student Achievement.

    ERIC Educational Resources Information Center

    Sterbin, Allan; Rakow, Ernest

    The direct effects of locus of control and self-esteem on standardized test scores were studied. The relationships among the standardized test scores and measures of locus of control and self-esteem for 12,260 students from the National Education Longitudinal Study 1994 database were examined, using the same definition of locus of control and…

  1. Locus of control and the fundamental dimensions of moods.

    PubMed

    Henson, H N; Chang, E C

    1998-06-01

    The present study examined the association between locus of control and positive and negative moods in 253 college students. Using the PANAS-X, designed by Watson and Clark, individuals scoring high on internal locus of control also scored higher across different dimensions of positive mood. Conversely, individuals scoring high on external locus of control had higher scores across different dimensions of negative mood.

  2. Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis.

    PubMed

    Frau, Maddalena; Feo, Francesco; Pascale, Rosa M

    2013-10-01

    Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post-transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC. Copyright © 2013 European Association for the Study of the Liver

  3. Neuroprotective and consequent neurorehabilitative clinical outcomes, in patients treated with the pleiotropic drug cerebrolysin

    PubMed Central

    Mureşanu, DF; Ciurea, AV; Chendreanu, CD; Mihaescu, AS; Mardare, DC; Andone, I; SpȦnu, A; Popescu, C; Dumitrescu, A; Popescu, M; Grigorean, V; Ungur, B; Marinescu, F; Colibaşeanu, I; Onose, L; Haras, M; Sandu, A; Spircu, T

    2009-01-01

    Background: Discovery of neurotrophic factors–emblematic: the nerve growth factor (NGF)–resulted in better approaching central nervous system (CNS) lesions. Recently, another crucial property has been unveiled: their rather unique pleiotropic effect. Cerebrolysin is a peptide mixture that penetrates the blood–brain barrier in significant amounts and mimics the effects of NGF. Methods: Comparative analysis: Cerebrolysin treated (10 ml x 2/ day, i.v. x 3 weeks) vs. non–treated, in patients (all received aside, a rather equivalent complementary, pharmacological and physical, therapy). Two lots of patients, admitted in our Physical and Rehabilitation (neural–muscular) Medical–PR(n–m)M–Clinic Division, during 2007–2009: 69 treated with Cerebrolysin (22 F, 47 M; Average: 59.333; Mean of age: 61.0 Years old; Standard deviation 16.583) and 70 controls (41 F, 29 M; A: 70.014; M.o.a.: 70.5 Y.o.; S.d.: 6.270) were studied. The total number of assessed items was 13: most contributive in relation with the score of Functional Independence Measure at discharge (d FIM), were: admission (a FIM), number of physical therapy days (PT), number of hospitalization days (H), age (A) and–relatively–days until the first knee functional extension (KE). Concomitantly, the main/ key, focused on neuro–motor rehabilitative outcomes, functional/analytical parameters, have been assessed regarding the speed in achieving their functional recovery. Results: Concerning d FIM, there have not been objectified significant differences between the two lots (p=0.2453) but regarding key, focused on neuro–motor rehabilitative outcomes, functional/analytical parameters: KE (p=0.0007) and days until the first time recovery of the ability to walk between parallel bars (WPB–p=0.0000)–highly significant differences in favor of Cerebrolysin lot resulted. Conclusion: Cerebrolysin administration, as neurorehabilitative outcomes, proved to hasten, statistically significant, especially the

  4. Pleiotropic effects of hexavalent chromium (CrVI) in Mytilus galloprovincialis digestive gland.

    PubMed

    Barmo, Cristina; Ciacci, Caterina; Fabbri, Rita; Olivieri, Silvia; Bianchi, Nicola; Gallo, Gabriella; Canesi, Laura

    2011-05-01

    observed in both sexes. The results demonstrate that exposure to Cr(VI) in the low ppb range did not result in strong toxicity or oxidative stress conditions in mussel digestive gland. On the other hand, our data support the hypothesis that low concentrations of the metal can exert pleiotropic effects on mussel physiology, from modulation of lipid and carbohydrate metabolism, to effects on the expression of estrogen-responsive genes.

  5. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.

    PubMed

    Vallon, Volker; Thomson, Scott C

    2017-02-01

    also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

  6. The human growth hormone gene is regulated by a multicomponent locus control region

    SciTech Connect

    Jones, B.; Cooke, N.E.; Liebhaber, S.A.; Monks, B.R.

    1995-12-01

    This article describes research involving the five-member human growth hormone (hGH)/chorionic somatomammotropin (hCS) gene cluster and its expression in the placenta. The results indicate that interactions among multiple elements are required to restrict hGH transcription to the pituitary and generate appropriate levels of expression in the mouse genome. In addition, the results suggest a role for shared and unique regulatory sequences in locus control region-mediated expression of the hGH/hCS gene cluster in the pituitary and possibly the placenta. 67 refs., 9 figs.

  7. Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials.

    PubMed

    Balakumar, Pitchai; Dhanaraj, Sokkalingam A

    2013-09-01

    Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system.

  8. Statins Exert the Pleiotropic Effects Through Small GTP-Binding Protein Dissociation Stimulator Upregulation With a Resultant Rac1 Degradation

    PubMed Central

    Tanaka, Shin-ichi; Fukumoto, Yoshihiro; Nochioka, Kotaro; Minami, Tatsuro; Kudo, Shun; Shiba, Nobuyuki; Takai, Yoshimi; Williams, Carol L.; Liao, James K.; Shimokawa, Hiroaki

    2013-01-01

    Objective The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. Approach and Results In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II–induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II–induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol. Conclusions These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans. PMID:23640485

  9. Conserved Arrangement of Nested Genes at the Drosophila Gart Locus

    PubMed Central

    Henikoff, Steven; Eghtedarzadeh, Mohammad K.

    1987-01-01

    The Drosophila melanogaster Gart gene encodes three enzymatic activities in the pathway for purine de novo synthesis. Alternative processing of the primary transcript leads to the synthesis of two overlapping polypeptides. The coding sequence for both polypeptides is interrupted by an intron that contains a functional cuticle protein gene encoded on the opposite DNA strand. Here we show that this nested organization also exists at the homologous locus of a distantly related species, Drosophila pseudoobscura. In both species, the intronic cuticle gene is expressed in wandering larvae and in prepupae. Remarkably, there are 24 different highly conserved noncoding segments within the intron containing the cuticle gene. These are found upstream of the transcriptional start, at the 3' end, and even within the single intronic gene intron. Other introns in the purine gene, including the intron at which alternative processing occurs, show no such homologies. It seems likely that at least some of the conserved noncoding regions are involved in specifying the high level developmental expression of the cuticle gene. We discuss the possibility that shared cis-acting regulatory sites might enhance transcription of both genes and help explain their nested arrangement. PMID:3123310

  10. Genetic variability at the PARK16 locus

    PubMed Central

    Tucci, Arianna; Nalls, Mike A; Houlden, Henry; Revesz, Tamas; Singleton, Andrew B; Wood, Nicholas W; Hardy, John; Paisán-Ruiz, Coro

    2010-01-01

    Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case–control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process. PMID:20683486

  11. Molecular Identification of the Schwannomatosis Locus

    DTIC Science & Technology

    2004-07-01

    AD Award Number: DAMD17-03-1-0445 TITLE: Molecular Identification of the Schwannomatosis Locus PRINCIPAL INVESTIGATOR: Mia M. MacCollin, M.D...COVERED (Leave blank) July 2004 Annual (1 Jul 2003 - 30 Jun 2004) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Molecular Identification of the Schwannomatosis...linkage and loss of heterozygosity analyses. 3. To determine the molecular mechanism of tumor formation in these patients using complementary molecular

  12. Bipolar disorder: evidence for a major locus.

    PubMed

    Spence, M A; Flodman, P L; Sadovnick, A D; Bailey-Wilson, J E; Ameli, H; Remick, R A

    1995-10-09

    Complex segregation analyses were conducted on families of bipolar I and bipolar II probands to delineate the mode of inheritance. The probands were ascertained from consecutive referrals to the Mood Disorder Service, University Hospital, University of British Columbia and diagnosed by DSM-III-R and Research Diagnostic Criteria. Data were available on over 1,500 first-degree relatives of the 186 Caucasian probands. The purpose of the analyses was to determine if, after correcting for age and birth cohort, there was evidence for a single major locus. Five models were fit to the data using the statistical package SAGE: i) dominant, ii) recessive, iii) arbitrary mendelian inheritance, iv) environmental, and v) no major effects. A single dominant, mendelian major locus was the best fitting of these models for the sample of bipolar I and II probands when only bipolar relatives were defined as affected (polygenic inheritance could not be tested). Adding recurrent major depression to the diagnosis "affected" for relatives reduced the evidence for a major locus effect. Our findings support the undertaking of linkage studies and are consistent with the analyses of the National Institutes of Mental Health (NIMH) Collaborative Study data by Rice et al. (Arch Gen Psychiatry 44: 441-447, 1987) and Blangero and Elston (Genet Epidemiol 6:221-227, 1989).

  13. Bipolar disorder: Evidence for a major locus

    SciTech Connect

    Spence, M.A.; Flodman, P.L.; Sadovnick, A.D.; Ameli, H.

    1995-10-09

    Complex segregation analyses were conducted on families of bipolar I and bipolar II probands to delineate the mode of inheritance. The probands were ascertained from consecutive referrals to the Mood Disorder Service, University Hospital, University of British Columbia and diagnosed by DSM-III-R and Research Diagnostic Criteria. Data were available on over 1,500 first-degree relatives of the 186 Caucasian probands. The purpose of the analyses was to determine if, after correcting for age and birth cohort, there was evidence for a single major locus. Five models were fit to the data using the statistical package SAGE: (1) dominant, (2) recessive, (3) arbitrary mendelian inheritance, (4) environmental, and (5) no major effects. A single dominant, mendelian major locus was the best fitting of these models for the sample of bipolar I and II probands when only bipolar relatives were defined as affected (polygenic inheritance could not be tested). Adding recurrent major depression to the diagnosis {open_quotes}affected{close_quotes} for relatives reduced the evidence for a major locus effect. Our findings support the undertaking of linkage studies and are consistent with the analyses of the National Institutes of Mental Health (NIMH) Collaborative Study data by Rice et al. and Blangero and Elston. 39 refs., 4 tabs.

  14. The pleiotropic effects of phosphodiesterase 5 inhibitors on function and safety in patients with cardiovascular disease and hypertension.

    PubMed

    Chrysant, Steven G; Chrysant, George S

    2012-09-01

    Phosphodiesterase 5 (PDE-5) inhibitors are selective blockers of PDE-5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP) to its corresponding monophosphates. cGMP is a potent vasodilator and nitric oxide donor. Since PDE-5 is widely distributed in the body, it was hypothesized that inhibition of its actions could lead to significant vasodilation, which could benefit patients with coronary artery disease. This hypothesis led to the development of PDE-5 inhibitors, the first being sildenafil citrate. Studies of sildenafil in patients with coronary artery disease demonstrated a modest cardiovascular effect but a potent action on penile erection in men, resulting in sildenafil becoming first-line treatment of erectile dysfunction. Two more PDE-5 inhibitors are now US Food and Drug Administration-approved (vardenafil and tadalafil) for the treatment of erectile dysfunction. Recent studies have demonstrated several beneficial pleiotropic cardiovascular effects of PDE-5 inhibitors in patients with erectile dysfunction and multiple comorbidities, including coronary artery disease, heart failure, hypertension, and diabetes mellitus. Treatment of these conditions with PDE-5 inhibitors has been very effective, safe, and well tolerated. Drug interactions have been minimal with the exception of nitrates, where coadministration may result in severe vasodilation and hypotension. These beneficial pleiotropic and safe cardiovascular effects of PDE-5 inhibitors will be discussed in this concise review. © 2012 Wiley Periodicals, Inc.

  15. Activation of the Pleiotropic Drug Resistance Pathway Can Promote Mitochondrial DNA Retention by Fusion-Defective Mitochondria in Saccharomyces cerevisiae

    PubMed Central

    Mutlu, Nebibe; Garipler, Görkem; Akdoğan, Emel; Dunn, Cory D.

    2014-01-01

    Genetic and microscopic approaches using Saccharomyces cerevisiae have identified many proteins that play a role in mitochondrial dynamics, but it is possible that other proteins and pathways that play a role in mitochondrial division and fusion remain to be discovered. Mutants lacking mitochondrial fusion are characterized by rapid loss of mitochondrial DNA. We took advantage of a petite-negative mutant that is unable to survive mitochondrial DNA loss to select for mutations that allow cells with fusion-deficient mitochondria to maintain the mitochondrial genome on fermentable medium. Next-generation sequencing revealed that all identified suppressor mutations not associated with known mitochondrial division components were localized to PDR1 or PDR3, which encode transcription factors promoting drug resistance. Further studies revealed that at least one, if not all, of these suppressor mutations dominantly increases resistance to known substrates of the pleiotropic drug resistance pathway. Interestingly, hyperactivation of this pathway did not significantly affect mitochondrial shape, suggesting that mitochondrial division was not greatly affected. Our results reveal an intriguing genetic connection between pleiotropic drug resistance and mitochondrial dynamics. PMID:24807265

  16. Activation of the pleiotropic drug resistance pathway can promote mitochondrial DNA retention by fusion-defective mitochondria in Saccharomyces cerevisiae.

    PubMed

    Mutlu, Nebibe; Garipler, Görkem; Akdoğan, Emel; Dunn, Cory D

    2014-05-07

    Genetic and microscopic approaches using Saccharomyces cerevisiae have identified many proteins that play a role in mitochondrial dynamics, but it is possible that other proteins and pathways that play a role in mitochondrial division and fusion remain to be discovered. Mutants lacking mitochondrial fusion are characterized by rapid loss of mitochondrial DNA. We took advantage of a petite-negative mutant that is unable to survive mitochondrial DNA loss to select for mutations that allow cells with fusion-deficient mitochondria to maintain the mitochondrial genome on fermentable medium. Next-generation sequencing revealed that all identified suppressor mutations not associated with known mitochondrial division components were localized to PDR1 or PDR3, which encode transcription factors promoting drug resistance. Further studies revealed that at least one, if not all, of these suppressor mutations dominantly increases resistance to known substrates of the pleiotropic drug resistance pathway. Interestingly, hyperactivation of this pathway did not significantly affect mitochondrial shape, suggesting that mitochondrial division was not greatly affected. Our results reveal an intriguing genetic connection between pleiotropic drug resistance and mitochondrial dynamics. Copyright © 2014 Mutlu et al.

  17. The Mutation of Glu at Amino Acid 3838 of AtMDN1 Provokes Pleiotropic Developmental Phenotypes in Arabidopsis

    PubMed Central

    Li, Peng-Cheng; Yu, Shao-Wei; Li, Ke; Huang, Jin-Guang; Wang, Xing-Jun; Zheng, Cheng-Chao

    2016-01-01

    MDN1/Rea1, as an AAA-type ATPase, is predicted to be the largest protein involved in pre-ribosome maturation in most organisms. However, its function in plant growth and development is poorly understood. Here, we characterized a novel Arabidopsis mutant, dwarf & short root (dsr) 1, which shows pleiotropic developmental phenotypes, such as slow germination, short root, dwarf shoot, and reduced seed set under normal growth conditions. Using positional cloning, we revealed that the AtMDN1 function is impaired by a ‘glutamic acid’ to ‘lysine’ change at position 3838 of the amino acid sequence in dsr1. Multiple sequence alignment analysis revealed that the mutated Glu residue, which located in the linker domain of AtMDN1, is extremely conserved among organisms. AtMDN1 is expressed in various tissues, particularly in the shoot apex and root tip. Moreover, the results of transcript profile analyses showed that the dysfunction of AtMDN1 in dsr1 impairs the expression of genes related to plant growth and development, which is tightly associated with the pleiotropic phenotypes of dsr1. Thus, we concluded that the Glu residue plays a vital role in maintaining AtMDN1 functions, which are essential for plant growth and development. PMID:27824150

  18. The effects of becoming taller: direct and pleiotropic effects of artificial selection on plant height in Brassica rapa.

    PubMed

    Zu, Pengjuan; Schiestl, Florian P

    2017-03-01

    Plant height is an important trait for plant reproductive success. Plant height is often under pollinator-mediated selection, and has been shown to be correlated with various other traits. However, few studies have examined the evolutionary trajectory of plant height under selection and the pleiotropic effects of plant height evolution. We conducted a bi-directional artificial selection experiment on plant height with fast cycling Brassica rapa plants to estimate its heritability and genetic correlations, and to reveal evolutionary responses to artificial selection on height and various correlated traits. With the divergent lines obtained through artificial selection, we subsequently conducted pollinator-choice assays and investigated resource limitation of fruit production. We found that plant height variation is strongly genetically controlled (with a realized heritability of 41-59%). Thus, plant height can evolve rapidly under phenotypic selection. In addition, we found remarkable pleiotropic effects in phenology, morphology, floral scent, color, nectar and leaf glucosinolates. Most traits were increased in tall-line plants, but flower size, UV reflection and glucosinolates were decreased, indicating potential trade-offs. Pollinators preferred plants of the tall selection lines over the short selection lines in both greenhouse experiments with bumblebees and field experiment with natural pollinators. We did not detect any differences in resource limitation between plants of the different selection lines. Overall, our study predicts that increased height should evolve under positive pollinator-mediated directional selection with potential trade-offs in floral signals and herbivore defense.

  19. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

    PubMed

    Deelen, Joris; Beekman, Marian; Uh, Hae-Won; Broer, Linda; Ayers, Kristin L; Tan, Qihua; Kamatani, Yoichiro; Bennet, Anna M; Tamm, Riin; Trompet, Stella; Guðbjartsson, Daníel F; Flachsbart, Friederike; Rose, Giuseppina; Viktorin, Alexander; Fischer, Krista; Nygaard, Marianne; Cordell, Heather J; Crocco, Paolina; van den Akker, Erik B; Böhringer, Stefan; Helmer, Quinta; Nelson, Christopher P; Saunders, Gary I; Alver, Maris; Andersen-Ranberg, Karen; Breen, Marie E; van der Breggen, Ruud; Caliebe, Amke; Capri, Miriam; Cevenini, Elisa; Collerton, Joanna C; Dato, Serena; Davies, Karen; Ford, Ian; Gampe, Jutta; Garagnani, Paolo; de Geus, Eco J C; Harrow, Jennifer; van Heemst, Diana; Heijmans, Bastiaan T; Heinsen, Femke-Anouska; Hottenga, Jouke-Jan; Hofman, Albert; Jeune, Bernard; Jonsson, Palmi V; Lathrop, Mark; Lechner, Doris; Martin-Ruiz, Carmen; Mcnerlan, Susan E; Mihailov, Evelin; Montesanto, Alberto; Mooijaart, Simon P; Murphy, Anne; Nohr, Ellen A; Paternoster, Lavinia; Postmus, Iris; Rivadeneira, Fernando; Ross, Owen A; Salvioli, Stefano; Sattar, Naveed; Schreiber, Stefan; Stefánsson, Hreinn; Stott, David J; Tiemeier, Henning; Uitterlinden, André G; Westendorp, Rudi G J; Willemsen, Gonneke; Samani, Nilesh J; Galan, Pilar; Sørensen, Thorkild I A; Boomsma, Dorret I; Jukema, J Wouter; Rea, Irene Maeve; Passarino, Giuseppe; de Craen, Anton J M; Christensen, Kaare; Nebel, Almut; Stefánsson, Kári; Metspalu, Andres; Magnusson, Patrik; Blanché, Hélène; Christiansen, Lene; Kirkwood, Thomas B L; van Duijn, Cornelia M; Franceschi, Claudio; Houwing-Duistermaat, Jeanine J; Slagboom, P Eline

    2014-08-15

    The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated. © The Author 2014. Published by Oxford University Press.

  20. A gene locus for targeted ectopic gene integration in Zymoseptoria tritici☆

    PubMed Central

    Kilaru, S.; Schuster, M.; Latz, M.; Das Gupta, S.; Steinberg, N.; Fones, H.; Gurr, S.J.; Talbot, N.J.; Steinberg, G.

    2015-01-01

    Understanding the cellular organization and biology of fungal pathogens requires accurate methods for genomic integration of mutant alleles or fluorescent fusion-protein constructs. In Zymoseptoria tritici, this can be achieved by integrating of plasmid DNA randomly into the genome of this wheat pathogen. However, untargeted ectopic integration carries the risk of unwanted side effects, such as altered gene expression, due to targeting regulatory elements, or gene disruption following integration into protein-coding regions of the genome. Here, we establish the succinate dehydrogenase (sdi1) locus as a single “soft-landing” site for targeted ectopic integration of genetic constructs by using a carboxin-resistant sdi1R allele, carrying the point-mutation H267L. We use various green and red fluorescent fusion constructs and show that 97% of all transformants integrate correctly into the sdi1 locus as single copies. We also demonstrate that such integration does not affect the pathogenicity of Z. tritici, and thus the sdi1 locus is a useful tool for virulence analysis in genetically modified Z. tritici strains. Furthermore, we have developed a vector which facilitates yeast recombination cloning and thus allows assembly of multiple overlapping DNA fragments in a single cloning step for high throughput vector and strain generation. PMID:26092798

  1. FLOWERING LOCUS T duplication coordinates reproductive and vegetative growth in perennial poplar.

    PubMed

    Hsu, Chuan-Yu; Adams, Joshua P; Kim, Hyejin; No, Kyoungok; Ma, Caiping; Strauss, Steven H; Drnevich, Jenny; Vandervelde, Lindsay; Ellis, Jeffrey D; Rice, Brandon M; Wickett, Norman; Gunter, Lee E; Tuskan, Gerald A; Brunner, Amy M; Page, Grier P; Barakat, Abdelali; Carlson, John E; DePamphilis, Claude W; Luthe, Dawn S; Yuceer, Cetin

    2011-06-28

    Annual plants grow vegetatively at early developmental stages and then transition to the reproductive stage, followed by senescence in the same year. In contrast, after successive years of vegetative growth at early ages, woody perennial shoot meristems begin repeated transitions between vegetative and reproductive growth at sexual maturity. However, it is unknown how these repeated transitions occur without a developmental conflict between vegetative and reproductive growth. We report that functionally diverged paralogs FLOWERING LOCUS T1 (FT1) and FLOWERING LOCUS T2 (FT2), products of whole-genome duplication and homologs of Arabidopsis thaliana gene FLOWERING LOCUS T (FT), coordinate the repeated cycles of vegetative and reproductive growth in woody perennial poplar (Populus spp.). Our manipulative physiological and genetic experiments coupled with field studies, expression profiling, and network analysis reveal that reproductive onset is determined by FT1 in response to winter temperatures, whereas vegetative growth and inhibition of bud set are promoted by FT2 in response to warm temperatures and long days in the growing season. The basis for functional differentiation between FT1 and FT2 appears to be expression pattern shifts, changes in proteins, and divergence in gene regulatory networks. Thus, temporal separation of reproductive onset and vegetative growth into different seasons via FT1 and FT2 provides seasonality and demonstrates the evolution of a complex perennial adaptive trait after genome duplication.

  2. FLOWERING LOCUS T duplication coordinates reproductive and vegetative growth in perennial poplar

    PubMed Central

    Hsu, Chuan-Yu; Adams, Joshua P.; Kim, Hyejin; No, Kyoungok; Ma, Caiping; Strauss, Steven H.; Drnevich, Jenny; Vandervelde, Lindsay; Ellis, Jeffrey D.; Rice, Brandon M.; Wickett, Norman; Gunter, Lee E.; Tuskan, Gerald A.; Brunner, Amy M.; Page, Grier P.; Barakat, Abdelali; Carlson, John E.; dePamphilis, Claude W.; Luthe, Dawn S.; Yuceer, Cetin

    2011-01-01

    Annual plants grow vegetatively at early developmental stages and then transition to the reproductive stage, followed by senescence in the same year. In contrast, after successive years of vegetative growth at early ages, woody perennial shoot meristems begin repeated transitions between vegetative and reproductive growth at sexual maturity. However, it is unknown how these repeated transitions occur without a developmental conflict between vegetative and reproductive growth. We report that functionally diverged paralogs FLOWERING LOCUS T1 (FT1) and FLOWERING LOCUS T2 (FT2), products of whole-genome duplication and homologs of Arabidopsis thaliana gene FLOWERING LOCUS T (FT), coordinate the repeated cycles of vegetative and reproductive growth in woody perennial poplar (Populus spp.). Our manipulative physiological and genetic experiments coupled with field studies, expression profiling, and network analysis reveal that reproductive onset is determined by FT1 in response to winter temperatures, whereas vegetative growth and inhibition of bud set are promoted by FT2 in response to warm temperatures and long days in the growing season. The basis for functional differentiation between FT1 and FT2 appears to be expression pattern shifts, changes in proteins, and divergence in gene regulatory networks. Thus, temporal separation of reproductive onset and vegetative growth into different seasons via FT1 and FT2 provides seasonality and demonstrates the evolution of a complex perennial adaptive trait after genome duplication. PMID:21653885

  3. Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus.

    PubMed

    Perez-Nanclares, Gustavo; Romanelli, Valeria; Mayo, Sonia; Garin, Intza; Zazo, Celia; Fernandez-Rebollo, Eduardo; Martínez, Francisco; Lapunzina, Pablo; de Nanclares, Guiomar Pérez

    2012-06-01

    Genomic imprinting is the modification of the genome so that genes from only one (rather than two) of the parental alleles are expressed. The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects. Our objective was to identify multilocus imprinting defects and characterize any mutations in trans-acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus. We have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20. We found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes. Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.

  4. A Functional and Structural Analysis of the Sex Combs Reduced Locus of Drosophila Melanogaster

    PubMed Central

    Pattatucci, A. M.; Otteson, D. C.; Kaufman, T. C.

    1991-01-01

    We have undertaken a developmental genetic analysis of the homeotic gene Sex combs reduced (Scr) of Drosophila melanogaster by examining embryonic and adult phenotypes of mutations affecting Scr gene function. Molecular mapping of Scr breakpoint lesions has defined a segment of >70 kb of DNA necessary for proper Scr gene function. This region is split by the fushi tarazu (ftz) gene, with lesions affecting embryonic Scr function molecularly mapping to the region proximal (5') to ftz and those exhibiting polyphasic semilethality predominantly mapping distal (3') to ftz. Gain-of-function mutations are associated with genomic rearrangements and map throughout the Scr locus. Our analysis has revealed that the Scr locus encompasses genetic elements that are responsible for functions in both the embryonic and larval to adult periods of development. From these studies, we conclude that Scr is a complex genetic locus with an extensive regulatory region that directs functions required for normal head and thoracic development in both the embryo and the adult and that the regulation of Scr during these two periods is distinct. PMID:1743486

  5. Locus-Specific DNA Methylation Reprogramming During Early Porcine Embryogenesis1

    PubMed Central

    Zhao, Ming-Tao; Rivera, Rocio M.; Prather, Randall S.

    2013-01-01

    ABSTRACT During early mammalian embryogenesis, there is a wave of DNA demethylation postfertilization and de novo methylation around implantation. The paternal genome undergoes active DNA demethylation, whereas the maternal genome is passively demethylated after fertilization in most mammals except for sheep and rabbits. However, the emerging genome-wide DNA methylation landscape has revealed a regulatory and locus-specific DNA methylation reprogramming pattern in mammalian preimplantation embryos. Here we optimized a bisulfite sequencing protocol to draw base-resolution DNA methylation profiles of several selected genes in gametes, early embryos, and somatic tissue. We observed locus-specific DNA methylation reprogramming in early porcine embryos. First, some pluripotency genes (POU5F1 and NANOG) followed a typical wave of DNA demethylation and remethylation, whereas CpG-rich regions of SOX2 and CDX2 loci were hypomethylated throughout development. Second, a differentially methylated region of an imprint control region in the IGF2/H19 locus exhibited differential DNA methylation which was maintained in porcine early embryos. Third, a centromeric repeat element retained a moderate DNA methylation level in gametes, early embryos, and somatic tissue. The diverse DNA methylation reprogramming during early embryogenesis is thought to be possibly associated with the multiple functions of DNA methylation in transcriptional regulation, genome stability and genomic imprinting. The latest technology such as oxidative bisulfite sequencing to identify 5-hydroxymethylcytosine will further clarify the DNA methylation reprogramming during porcine embryonic development. PMID:23303676

  6. Atrial natriuretic peptide in the locus coeruleus and its possible role in the regulation of arterial blood pressure, fluid and electrolyte homeostasis

    SciTech Connect

    Geiger, H.; Sterzel, R.B. ); Bahner, U.; Heidland, A. ); Palkovits, M. )

    1991-01-01

    Atrial natriuretic factor (ANP) is present in neuronal cells of the locus coeruleus and its vicinity in the pontine tegmentum and moderate amount of ANP is detectable in this area by radioimmunoassay. The ANP is known as a neuropeptide which may influence the body salt and water homeostasis and blood pressure by targeting both central and peripheral regulatory mechanisms. Whether this pontine ANP cell group is involved in any of these regulatory mechanisms, the effect of various types of hypertension and experimental alterations in the salt and water balance on ANP levels was measured by radioimmunoassay in the locus coeruleus of rats. Adrenalectomy, as well as aldosterone and dexamethasone treatments failed to alter ANP levels in the locus coeruleus. Reduced ANP levels were measured in spontaneously hypertensive rats, and in diabetes insipidus rats with vasopressin replacement. In contrast to these situations, elevated ANP levels were found in rats with DOCA-salt or 1-Kidney-1-clip hypertension. These data suggest a link between ANP levels in the locus coeruleus and fluid volume homeostasis. Whether this link is causal and connected with the major activity of locus coeruleus neurons needs further information.

  7. Coordinate regulation of phospholipid biosynthesis in Saccharomyces cerevisiae: pleiotropically constitutive opi1 mutant.

    PubMed Central

    Klig, L S; Homann, M J; Carman, G M; Henry, S A

    1985-01-01

    Phospholipid metabolism in the Saccharomyces cerevisiae opi1 mutant, which excretes inositol and is constitutive for the biosynthetic enzyme inositol-1-phosphate synthase (M. Greenberg, P. Goldwasser, and S. Henry, Mol. Gen. Genet. 186:157-163, 1982), was examined and compared to that of a wild-type strain. In wild-type S. cerevisiae, the phospholipid composition and the relative rates of synthesis of individual phospholipids change in response to the availability of exogenous supplies of soluble phospholipid precursors, particularly inositol. The opi1 mutant, in contrast, displays a relatively invariant phospholipid composition, and its pattern of phospholipid synthesis does not change in response to exogenous phospholipid precursors. Phosphatidylinositol synthase was not found to be regulated in either wild-type or opi1 cells. In wild-type cells, phosphatidylserine synthase and the phospholipid N-methyltransferases are coordinately repressed in response to a combination of inositol and choline. However, in opi1 cells these activities are expressed constitutively. These results suggest that the gene product of the OPI1 locus participates in the coordinate regulation of phospholipid synthesis. Images PMID:3888957

  8. Enhanced Edar Signalling Has Pleiotropic Effects on Craniofacial and Cutaneous Glands

    PubMed Central

    Chang, Shie Hong; Jobling, Stephanie; Brennan, Keith; Headon, Denis J.

    2009-01-01

    The skin carries a number of appendages, including hair follicles and a range of glands, which develop under the influence of EDAR signalling. A gain of function allele of EDAR is found at high frequency in human populations of East Asia, with genetic evidence suggesting recent positive selection at this locus. The derived EDAR allele, estimated to have reached fixation more than 10,000 years ago, causes thickening of hair fibres, but the full spectrum of phenotypic changes induced by this allele is unknown. We have examined the changes in glandular structure caused by elevation of Edar signalling in a transgenic mouse model. We find that sebaceous and Meibomian glands are enlarged and that salivary and mammary glands are more elaborately branched with increased Edar activity, while the morphology of eccrine sweat and tracheal submucosal glands appears to be unaffected. Similar changes to gland sizes and structures may occur in human populations carrying the derived East Asian EDAR allele. As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways. PMID:19855838

  9. Enhanced Edar signalling has pleiotropic effects on craniofacial and cutaneous glands.

    PubMed

    Chang, Shie Hong; Jobling, Stephanie; Brennan, Keith; Headon, Denis J

    2009-10-26

    The skin carries a number of appendages, including hair follicles and a range of glands, which develop under the influence of EDAR signalling. A gain of function allele of EDAR is found at high frequency in human populations of East Asia, with genetic evidence suggesting recent positive selection at this locus. The derived EDAR allele, estimated to have reached fixation more than 10,000 years ago, causes thickening of hair fibres, but the full spectrum of phenotypic changes induced by this allele is unknown. We have examined the changes in glandular structure caused by elevation of Edar signalling in a transgenic mouse model. We find that sebaceous and Meibomian glands are enlarged and that salivary and mammary glands are more elaborately branched with increased Edar activity, while the morphology of eccrine sweat and tracheal submucosal glands appears to be unaffected. Similar changes to gland sizes and structures may occur in human populations carrying the derived East Asian EDAR allele. As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways.

  10. Regulatory RNAs in Planarians.

    PubMed

    Pawlicka, Kamila; Perrigue, Patrick M; Barciszewski, Jan

    2016-01-01

    The full scope of regulatory RNA evolution and function in epigenetic processes is still not well understood. The development of planarian flatworms to be used as a simple model organism for research has shown a great potential to address gaps in the knowledge in this field of study. The genomes of planarians encode a wide array of regulatory RNAs that function in gene regulation. Here, we review planarians as a suitable model organism for the identification and function of regulatory RNAs.

  11. A Mutation in a Purported Regulatory Gene Affects Control of Sterol Uptake in Saccharomyces cerevisiae

    PubMed Central

    Crowley, James H.; Leak, Frank W.; Shianna, Kevin V.; Tove, Shirley; Parks, Leo W.

    1998-01-01

    Aerobically growing wild-type strains of Saccharomyces cerevisiae are unable to take exogenously supplied sterols from media. This aerobic sterol exclusion is vitiated under anaerobic conditions, in heme-deficient strains, and under some conditions of impaired sterol synthesis. Mutants which can take up sterols aerobically in heme-competent cells have been selected. One of these mutations, designated upc2-1, gives a pleiotropic phenotype in characteristics as diverse as aerobic accumulation of sterols, total lipid storage, sensitivity to metabolic inhibitors, response to altered sterol structures, and cation requirements. During experiments designed to ascertain the effects of various cations on yeast with sterol alterations, it was observed that upc2-1 was hypersensitive to Ca2+. Using resistance to Ca2+ as a screening vehicle, we cloned UPC2 and showed that it is YDR213W, an open reading frame on chromosome IV. This belongs to a fungal regulatory family containing the Zn(II)2Cys6 binuclear cluster DNA binding domain. The single guanine-to-adenine transition in upc2-1 gives a predicted amino acid change from glycine to aspartic acid. The regulatory defect explains the semidominance and pleiotropic effects of upc2-1. PMID:9696767

  12. Regulatory Information By Sector

    EPA Pesticide Factsheets

    Find environmental regulatory, compliance, & enforcement information for various business, industry and government sectors, listed by NAICS code. Sectors include agriculture, automotive, petroleum manufacturing, oil & gas extraction & other manufacturing

  13. Nuclear receptor coactivator/coregulator NCoA6(NRC) is a pleiotropic coregulator involved in transcription, cell survival, growth and development

    PubMed Central

    Mahajan, Muktar A.; Samuels, Herbert H.

    2008-01-01

    NCoA6 (also referred to as NRC, ASC-2, TRBP, PRIP and RAP250) was originally isolated as a ligand-dependent nuclear receptor interacting protein. However, NCoA6 is a multifunctional coregulator or coactivator necessary for transcriptional activation of a wide spectrum of target genes. The NCoA6 gene is amplified and overexpressed in breast, colon and lung cancers. NCoA6 is a 250 kDa protein which harbors a potent N-terminal activation domain, AD1; and a second, centrally-located activation domain, AD2, which is necessary for nuclear receptor signaling. The intrinsic activation potential of NCoA6 is regulated by its C-terminal STL regulatory domain. Near AD2 is an LxxLL-1 motif which interacts with a wide spectrum of ligand-bound NRs with high-affinity. A second LxxLL motif (LxxLL-2) located towards the C-terminal region is more restricted in its NR specificity. The potential role of NCoA6 as a co-integrator is suggested by its ability to enhance transcriptional activation of a wide variety of transcription factors and from its in vivo association with a number of known cofactors including CBP/p300. NCoA6 has been shown to associate with at least three distinct coactivator complexes containing Set methyltransferases as core polypeptides. The composition of these complexes suggests that NCoA6 may play a fundamental role in transcriptional activation by modulating chromatin structure through histone methylation. Knockout studies in mice suggest that NCoA6 is an essential coactivator. NCoA6-/- embryos die between 8.5-12.5 dpc from general growth retardation coupled with developmental defects in the heart, liver, brain and placenta. NCoA6-/- MEFs grow at a reduced rate compared to WT MEFs and spontaneously undergo apoptosis, indicating the importance of NCoA6 as a prosurvival and anti-apoptotic gene. Studies with NCoA6+/- and conditional knockout mice suggest that NCoA6 is a pleiotropic coregulator involved in growth, development, wound healing and maintenance of energy

  14. Adapting in vitro embryonic stem cell differentiation to the study of locus control regions.

    PubMed

    Lahiji, Armin; Kučerová-Levisohn, Martina; Holmes, Roxanne; Zúñiga-Pflücker, Juan Carlos; Ortiz, Benjamin D

    2014-05-01

    Numerous locus control region (LCR) activities have been discovered in gene loci important to immune cell development and function. LCRs are a distinct class of cis-acting gene regulatory elements that appear to contain all the DNA sequence information required to establish an independently and predictably regulated gene expression program at any genomic site in native chromatin of a whole animal. As such, LCR-regulated transgenic reporter systems provide invaluable opportunities to investigate the mechanisms of gene regulatory DNA action during development. Furthermore the qualities of LCR-driven gene expression, including spatiotemporal specificity and "integration site-independence" would be highly desirable to incorporate into vectors used in therapeutic genetic engineering. Thus, advancement in the methods used to investigate LCRs is of considerable basic and translational significance. We study the LCR present in the mouse T cell receptor (TCR)-α gene locus. Until recently, transgenic mice provided the only experimental model capable of supporting the entire spectrum of LCR activities. We have recently reported complete manifestation of TCRα LCR function in T cells derived in vitro from mouse embryonic stem cells (ESC), thus validating a complete cell culture model for the full range of LCR activities seen in transgenic mice. Here we discuss the critical parameters involved in studying LCR-regulated gene expression during in vitro hematopoietic differentiation from ESCs. This advance provides an approach to speed progress in the LCR field, and facilitate the clinical application of its findings, particularly to the genetic engineering of T cells.

  15. Identification of three novel antisense RNAs in the fur locus from unicellular cyanobacteria.

    PubMed

    Sevilla, Emma; Martín-Luna, Beatriz; González, Andrés; Gonzalo-Asensio, Jesús A; Peleato, María Luisa; Fillat, María F

    2011-12-01

    The interplay between Fur (ferric uptake regulator) proteins and small, non-coding RNAs has been described as a key regulatory loop in several bacteria. In the filamentous cyanobacterium Anabaena sp. PCC 7120, a large dicistronic transcript encoding the putative membrane protein Alr1690 and an α-furA RNA is involved in the modulation of the global regulator FurA. In this work we report the existence of three novel antisense RNAs in cyanobacteria and show that a cis α-furA RNA is conserved in very different genomic contexts, namely in the unicellular cyanobacteria Microcystis aeruginosa PCC 7806 and Synechocystis sp. PCC 6803. Syα-fur RNA covers only part of the coding sequence of the fur orthologue sll0567, whose flanking genes encode two hypothetical proteins. Transcriptional analysis of fur and its adjacent genes in Microcystis unravels a highly compact organization of this locus involving overlapping transcripts. Maα-fur RNA spans the whole Mafur CDS and part of the flanking dnaJ and sufE sequences. In addition, Mafur seems to be part of a dicistronic operon encoding this regulator and an α-sufE RNA. These results allow new insights into the transcriptomes of two unicellular cyanobacteria and suggest that in M. aeruginosa PCC 7806, the α-fur and α-sufE RNAs might participate in a regulatory connection between the genes of the dnaJ-fur-sufE locus.

  16. Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25.

    PubMed

    Ebana, Yusuke; Ozaki, Kouichi; Liu, Lian; Hachiya, Hitoshi; Hirao, Kenzo; Isobe, Mitsuaki; Kubo, Michiaki; Tanaka, Toshihiro; Furukawa, Tetsushi

    2017-10-01

    Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p=0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p<0.0001, p<0.005, respectively). AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  17. Characterization of a hypoxia-response element in the Epo locus of the pufferfish, Takifugu rubripes.

    PubMed

    Kulkarni, Rashmi P; Tohari, Sumanty; Ho, Adrian; Brenner, Sydney; Venkatesh, Byrappa

    2010-06-01

    Animals respond to hypoxia by increasing synthesis of the glycoprotein hormone erythropoietin (Epo) which in turn stimulates the production of red blood cells. The gene encoding Epo has been recently cloned in teleost fishes such as the pufferfish Takifugu rubripes (fugu) and zebrafish (Danio rerio). It has been shown that the transcription levels of Epo in teleost fishes increase in response to anemia or hypoxia in a manner similar to its human ortholog. However, the cis-regulatory element(s) mediating the hypoxia response of Epo gene in fishes has not been identified. In the present study, using the human hepatoma cell line (Hep3B), we have identified and characterized a hypoxia response element (HRE) in the fugu Epo locus. The sequence of the fugu HRE (ACGTGCTG) is identical to that of the HRE in the human EPO locus. However, unlike the HRE in the mammalian Epo locus, which is located in the 3' region of the gene, the fugu HRE is located in the 5' flanking region and on the opposite strand of DNA. This HRE is conserved in other teleosts such as Tetraodon and zebrafish in a similar location. A 365-bp fragment containing the fugu HRE was able to drive GFP expression in the liver of transgenic zebrafish. However, we could not ascertain if the expression of transgene is induced by hypoxia in vivo due to the low and variable levels of GFP expression in transgenic zebrafish. Our investigations also revealed that the Epo locus has experienced extensive rearrangements during vertebrate evolution.

  18. Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson's Disease Locus.

    PubMed

    Labbé, Catherine; Ogaki, Kotaro; Lorenzo-Betancor, Oswaldo; Carrasquillo, Minerva M; Heckman, Michael G; McCarthy, Allan; Soto-Ortolaza, Alexandra I; Walton, Ronald L; Lynch, Timothy; Siuda, Joanna; Opala, Grzegorz; Krygowska-Wajs, Anna; Barcikowska, Maria; Czyzewski, Krzysztof; Dickson, Dennis W; Uitti, Ryan J; Wszolek, Zbigniew K; Ross, Owen A

    2015-01-01

    Genome-wide association studies (GWAS) in Parkinson's disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11-1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.

  19. A root locus based flutter synthesis procedure

    NASA Technical Reports Server (NTRS)

    Hajela, P.

    1983-01-01

    An efficient generalized constraint is proposed in the context of a nonlinear mathematical programming approach for the minimum weight design of wing structures for flutter considerations. The approach is based on a root locus analysis procedure that is better suited for flutter redesign than the conventionally used V-g method. The proposed flutter constraint does not require an actual computation of the flutter speed, allows prescription of meaningful margins of safety in the optimized design and lends itself to elegant computation of sensitivity information. The approach is implemented and results presented for representative structural models.

  20. Root Locus Algorithms for Programmable Pocket Calculators

    NASA Technical Reports Server (NTRS)

    Wechsler, E. R.

    1983-01-01

    Two algorithms are described which allow the plotting of individual points on a root locus diagram with or without time delay. The development was performed during the design of a continuous phase shifter used in the Baseband Antenna Combiner for the Deep Space Network (DSN). The algorithms, which are expected to be useful in similar DSN efforts, are simple enough to be implemented on a programmable pocket calculator. The coordinates of the open-loop zeros and poles, the gain constant K, and the time delay T are the data inputs.

  1. A model for antagonistic pleiotropic gene action for mortality and advanced age.

    PubMed Central

    Toupance, B; Godelle, B; Gouyon, P H; Schächter, F

    1998-01-01

    Association or linkage studies involving control and long-lived populations provide information on genes that influence longevity. However, the relationship between allele-specific differences in survival and the genetic structure of aging cohorts remains unclear. We model a heterogeneous cohort comprising several genotypes differing in age-specific mortality. In its most general form, without any specific assumption regarding the shape of mortality curves, the model permits derivation of a fundamental property underlying abrupt age-related changes in the composition of a cohort. The model is applied to sex-specific survival curves taken from period life tables, and Gompertz-Makeham mortality coefficients are calculated for the French population. Then, adjustments are performed under Gompertz-Makeham mortality functions for three genotypes composing a heterogeneous cohort, under the constraint of fitting the resultant mortality to the real French population mortality obtained from life tables. Multimodal curves and divergence after the 8th decade appear as recurrent features of the frequency trajectories. Finally, a fit to data previously obtained at the angiotensin-converting-enzyme locus is realized, explaining what had seemed to be paradoxical results-namely, that the frequency of a genotype known as a cardiovascular risk factor was increased in centenarians. Our results help explain the well-documented departure from Gompertz-Makeham mortality kinetics at older ages. The implications of our model are discussed in the context of known genetic effects on human longevity and age-related pathologies. Since antagonistic pleiotropy between early and late survival emerges as a general rule, extrapolating the effects measured for a gene in a particular age class to other ages could be misleading. PMID:9585593

  2. A new regulatory principle for in vivo biochemistry: pleiotropic low affinity regulation by the adenine nucleotides--illustrated for the glycolytic enzymes of Saccharomyces cerevisiae.

    PubMed

    Mensonides, Femke I C; Bakker, Barbara M; Cremazy, Frederic; Messiha, Hanan L; Mendes, Pedro; Boogerd, Fred C; Westerhoff, Hans V

    2013-09-02

    Enzymology tends to focus on highly specific effects of substrates, allosteric modifiers, and products occurring at low concentrations, because these are most informative about the enzyme's catalytic mechanism. We hypothesized that at relatively high in vivo concentrations, important molecular monitors of the state of living cells, such as ATP, affect multiple enzymes of the former and that these interactions have gone unnoticed in enzymology. We test this hypothesis in terms of the effect that ATP, ADP, and AMP might have on the major free-energy delivering pathway of the yeast Saccharomyces cerevisiae. Assaying cell-free extracts, we collected a comprehensive set of quantitative kinetic data concerning the enzymes of the glycolytic and the ethanol fermentation pathways. We determined systematically the extent to which the enzyme activities depend on the concentrations of the adenine nucleotides. We found that the effects of the adenine nucleotides on enzymes catalysing reactions in which they are not directly involved as substrate or product, are substantial. This includes effects on the Michaelis-Menten constants, adding new perspective on these, 100 years after their introduction.

  3. Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations.

    PubMed

    Fusco, Francesca; Pescatore, Alessandra; Bal, Elodie; Ghoul, Aida; Paciolla, Mariateresa; Lioi, Maria Brigida; D'Urso, Michele; Rabia, Smail Hadj; Bodemer, Christine; Bonnefont, Jean Paul; Munnich, Arnold; Miano, Maria Giuseppina; Smahi, Asma; Ursini, Matilde Valeria

    2008-05-01

    Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP- and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (>65%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families.

  4. Pleiotropic action of insulin-like peptides of mollusk, Anodonta cygnea.

    PubMed

    Shipilov, V N; Shpakov, A O; Rusakov, Yu I

    2005-04-01

    Insulin-related peptides (IRPs) from ganglions of mollusk, Anodonta cygnea, were purified and characterized (IRP1-IRP13) using insulin and insulin-like growth factor-I (IGF-I) radioreceptor test systems. The IRPs were able to bind to insulin and IGF-I receptors. Dose-dependent curve slopes indicated that most IRPs bind with higher affinity to IGF-I receptors than to insulin receptors. The IRP regulatory action on the activity of the adenylyl cyclase signal system showed that these peptides stimulated adenylyl cyclase and GTP-binding activity of G-proteins to the same extent as insulin and IGF-I. The data obtained suggest polyfunctional IRP action that apparently is determined by the molecular structure of individual isoforms.

  5. Relationships between locus of control and paranormal beliefs.

    PubMed

    Newby, Robert W; Davis, Jessica Boyette

    2004-06-01

    The present study investigated the associations between scores on paranormal beliefs, locus of control, and certain psychological processes such as affect and cognitions as measured by the Linguistic Inquiry and Word Count. Analysis yielded significant correlations between scores on Locus of Control and two subscales of Tobacyk's (1988) Revised Paranormal Beliefs Scale, New Age Philosophy and Traditional Paranormal Beliefs. A step-wise multiple regression analysis indicated that Locus of Control was significantly related to New Age Philosophy. Other correlations were found between Tobacyk's subscales, Locus of Control, and three processes measured by the Linguistic Inquiry and Word Count.

  6. Impact of locus of control on health message effectiveness.

    PubMed

    Kong, Ying; Shen, Fuyuan

    2011-10-01

    This article examined how individuals' locus of control might moderate the effect of health message frames. An experiment was conducted whereby participants read either individual- or social-responsibility message frames after their locus of control was primed. Results indicated that messages presented in individual-responsibility frames were more persuasive when people were primed with internal locus of control, whereas social-responsibility framed appeals were more persuasive when people were primed with external locus of control. These results were found for individuals in both high and low cognitive load conditions. Theoretical and practical implications of the findings are discussed.

  7. Inside the CBF locus in Poaceae.

    PubMed

    Tondelli, Alessandro; Francia, Enrico; Barabaschi, Delfina; Pasquariello, Marianna; Pecchioni, Nicola

    2011-01-01

    Several molecular evidences have been gathered in Poaceae that point out a central role of the CBF/DREB1 transcription factors in the signal transduction pathways leading to low-temperature tolerance, although to a quite different extent between crops originating from either temperate or tropical climates. A common feature of the CBF/DREB1 genes in Poaceae is their structural organization at the genome level in clusters of tandemly duplicated genes. In temperate cereals such as barley and wheat, expansion of specific multigene phylogenetic clades of CBFs that map at the Frost Resistance-2 locus has been exclusively observed. In addition, copy number variants of CBF genes between frost resistant and frost sensitive genotypes raise the question if multiple copies of the CBF/DREB1s are required to ensure freezing tolerance. On the other hand, in crops of tropical origin such as rice and maize, a smaller or less-responsive CBF regulon may have evolved, and different mechanisms might determine chilling tolerance. In this review, recent advances on the organization and diversity at the CBF cluster locus in the grasses are provided and discussed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Data set for comparison of cellular dynamics between human AAVS1 locus-modified and wild-type cells

    PubMed Central

    Mizutani, Takeomi; Haga, Hisashi; Kawabata, Kazushige

    2016-01-01

    This data article describes cellular dynamics, such as migration speed and mobility of the cytoskeletal protein, of wild-type human fibroblast cells and cells with a modified adeno-associated virus integration site 1 (AAVS1) locus on human chromosome 19. Insertion of exogenous gene into the AAVS1 locus has been conducted in recent biological researches. Previously, our data showed that the AAVS1-modification changes cellular contractile force (Mizutani et al., 2015 [1]). To assess if this AAVS1-modification affects cell migration, we compared cellular migration speed and turnover of cytoskeletal protein in human fibroblasts and fibroblasts with a green fluorescent protein gene knocked-in at the AAVS1 locus in this data article. Cell nuclei were stained and changes in their position attributable to cell migration were analyzed. Fluorescence recovery was observed after photobleaching for the fluorescent protein-tagged myosin regulatory light chain. Data here are related to the research article “Transgene Integration into the Human AAVS1 Locus Enhances Myosin II-Dependent Contractile Force by Reducing Expression of Myosin Binding Subunit 85” [1]. PMID:26937449

  9. A multi-trait, meta-analysis for detecting pleiotropic polymorphisms for stature, fatness and reproduction in beef cattle.

    PubMed

    Bolormaa, Sunduimijid; Pryce, Jennie E; Reverter, Antonio; Zhang, Yuandan; Barendse, William; Kemper, Kathryn; Tier, Bruce; Savin, Keith; Hayes, Ben J; Goddard, Michael E

    2014-03-01

    Polymorphisms that affect complex traits or quantitative trait loci (QTL) often affect multiple traits. We describe two novel methods (1) for finding single nucleotide polymorphisms (SNPs) significantly associated with one or more traits using a multi-trait, meta-analysis, and (2) for distinguishing between a single pleiotropic QTL and multiple linked QTL. The meta-analysis uses the effect of each SNP on each of n traits, estimated in single trait genome wide association studies (GWAS). These effects are expressed as a vector of signed t-values (t) and the error covariance matrix of these t values is approximated by the correlation matrix of t-values among the traits calculated across the SNP (V). Consequently, t'V-1t is approximately distributed as a chi-squared with n degrees of freedom. An attractive feature of the meta-analysis is that it uses estimated effects of SNPs from single trait GWAS, so it can be applied to published data where individual records are not available. We demonstrate that the multi-trait method can be used to increase the power (numbers of SNPs validated in an independent population) of GWAS in a beef cattle data set including 10,191 animals genotyped for 729,068 SNPs with 32 traits recorded, including growth and reproduction traits. We can distinguish between a single pleiotropic QTL and multiple linked QTL because multiple SNPs tagging the same QTL show the same pattern of effects across traits. We confirm this finding by demonstrating that when one SNP is included in the statistical model the other SNPs have a non-significant effect. In the beef cattle data set, cluster analysis yielded four groups of QTL with similar patterns of effects across traits within a group. A linear index was used to validate SNPs having effects on multiple traits and to identify additional SNPs belonging to these four groups.

  10. Genome-wide comparative analyses of correlated and uncorrelated phenotypes identify major pleiotropic variants in dairy cattle.

    PubMed

    Xiang, Ruidong; MacLeod, Iona M; Bolormaa, Sunduimijid; Goddard, Michael E

    2017-08-23

    While single nucleotide polymorphisms (SNPs) associated with multiple phenotype have been reported, the knowledge of pleiotropy of uncorrelated phenotype is minimal. Principal components (PCs) and uncorrelated Cholesky transformed traits (CT) were constructed using 25 raw traits (RTs) of 2841 dairy bulls. Multi-trait meta-analyses of single-trait genome-wide association studies for RT, PC and CT in bulls were validated in 6821 cows. Most PCs and CTs had substantial estimates of heritability, suggesting that genes affect phenotype via diverse pathways. Phenotypic orthogonalizations did not eliminate pleiotropy: the meta-analysis achieved an agreement of significant pleiotropic SNPs (p < 1 × 10(-5), n = 368) between RTs (416), PCs (466) and CTs (425). From this overlap we identified 21 lead SNPs with 100% validation rate containing two clusters: one consisted of DGAT1 (chr14:1.8 M+), MGST1 (chr5:93 M+), PAEP (chr11:103 M+) and GPAT4 (chr27:36 M+) affecting protein, milk and fat yield and the other included CSN2 (chr6:87 M+), MUC1 (chr3:15.6 M), GHR (chr20:31.2 M+) and SDC2 (chr14:70 M+) affecting protein and milk yield. Combining beef cattle data identified correlated SNPs representing CAPN1 (chr29:44 M+) and CAST (chr 7:96 M+) loci affecting beef tenderness, showing pleiotropic effects in dairy cattle. Our findings show that SNPs with a large effect on one trait are likely to have small effects on other uncorrelated traits.

  11. A Multi-Trait, Meta-analysis for Detecting Pleiotropic Polymorphisms for Stature, Fatness and Reproduction in Beef Cattle

    PubMed Central

    Bolormaa, Sunduimijid; Pryce, Jennie E.; Reverter, Antonio; Zhang, Yuandan; Barendse, William; Kemper, Kathryn; Tier, Bruce; Savin, Keith; Hayes, Ben J.; Goddard, Michael E.

    2014-01-01

    Polymorphisms that affect complex traits or quantitative trait loci (QTL) often affect multiple traits. We describe two novel methods (1) for finding single nucleotide polymorphisms (SNPs) significantly associated with one or more traits using a multi-trait, meta-analysis, and (2) for distinguishing between a single pleiotropic QTL and multiple linked QTL. The meta-analysis uses the effect of each SNP on each of n traits, estimated in single trait genome wide association studies (GWAS). These effects are expressed as a vector of signed t-values (t) and the error covariance matrix of these t values is approximated by the correlation matrix of t-values among the traits calculated across the SNP (V). Consequently, t'V−1t is approximately distributed as a chi-squared with n degrees of freedom. An attractive feature of the meta-analysis is that it uses estimated effects of SNPs from single trait GWAS, so it can be applied to published data where individual records are not available. We demonstrate that the multi-trait method can be used to increase the power (numbers of SNPs validated in an independent population) of GWAS in a beef cattle data set including 10,191 animals genotyped for 729,068 SNPs with 32 traits recorded, including growth and reproduction traits. We can distinguish between a single pleiotropic QTL and multiple linked QTL because multiple SNPs tagging the same QTL show the same pattern of effects across traits. We confirm this finding by demonstrating that when one SNP is included in the statistical model the other SNPs have a non-significant effect. In the beef cattle data set, cluster analysis yielded four groups of QTL with similar patterns of effects across traits within a group. A linear index was used to validate SNPs having effects on multiple traits and to identify additional SNPs belonging to these four groups. PMID:24675618

  12. Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

    PubMed Central

    Lapchak, Paul A.

    2012-01-01

    The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their “drug-like” properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment. PMID:23687519

  13. Pleiotropic functions of embryonic sonic hedgehog expression link jaw and taste bud amplification with eye loss during cavefish evolution.

    PubMed

    Yamamoto, Yoshiyuki; Byerly, Mardi S; Jackman, William R; Jeffery, William R

    2009-06-01

    This study addresses the role of sonic hedgehog (shh) in increasing oral-pharyngeal constructive traits (jaws and taste buds) at the expense of eyes in the blind cavefish Astyanax mexicanus. In cavefish embryos, eye primordia degenerate under the influence of hyperactive Shh signaling. In concert, cavefish show amplified jaw size and taste bud numbers as part of a change in feeding behavior. To determine whether pleiotropic effects of hyperactive Shh signaling link these regressive and constructive traits, shh expression was compared during late development of the surface-dwelling (surface fish) and cave-dwelling (cavefish) forms of Astyanax. After an initial expansion along the midline of early embryos, shh was elevated in the oral-pharyngeal region in cavefish and later was confined to taste buds. The results of shh inhibition and overexpression experiments indicate that Shh signaling has an important role in oral and taste bud development. Conditional overexpression of an injected shh transgene at specific times in development showed that taste bud amplification and eye degeneration are sensitive to shh overexpression during the same early developmental period, although taste buds are not formed until much later. Genetic crosses between cavefish and surface fish revealed an inverse relationship between eye size and jaw size/taste bud number, supporting a link between oral-pharyngeal constructive traits and eye degeneration. The results suggest that hyperactive Shh signaling increases oral and taste bud amplification in cavefish at the expense of eyes. Therefore, selection for constructive oral-pharyngeal traits may be responsible for eye loss during cavefish evolution via pleiotropic function of the Shh signaling pathway.

  14. Murine fumarylacetoacetate hydrolase (Fah) gene is disrupted by a neonatally lethal albino deletion that defines the hepatocyte-specific developmental regulation 1 (hsdr-1) locus

    SciTech Connect

    Klebig, M.L. Oak Ridge National Lab., TN ); Russell, L.B.; Rinchik, E.M. )

    1992-02-15

    Homozygous deletion of the hepatocyte-specific developmental regulation 1 (hsdr-1) locus in mouse chromosome 7 results in perinatal death and a pleiotropic syndrome characterized by ultrastructural abnormalities of the liver and kidney, failure of induction of a number of specific transcription units in the liver and kidney during late gestation, and marked overexpression of an enzyme that defends against oxidative stress. Previously, the breakpoints of two albino (c) deletions (c{sup 14CoS} and c{sup IFAFyh}) that genetically define hsdr-1 were localized, on a long-range map, in the vicinity of the distal breakpoint of a viable albino deletion (c{sup 24R75M}) that breaks proximally within the c locus. Here the authors report the use of a probe derived from a deletion breakpoint fusion fragment cloned from c{sup 24R75M}/c{sup 24R75M} DNA to clone a breakpoint fusion fragment caused by the c{sup 14CoS} deletion. The proximal breakpoint of the c{sup 14CoS} deletion was discovered to disrupt a gene (Fah) encoding fumarylacetoacetate hydrolase, the last enzyme in the tyrosine degradation pathway. These mouse mutants may also provide models for the human genetic disorder hereditary tyrosinemia, which is associated with fumarylacetoacetate hydrolase deficiency and liver and kidney dysfunction.

  15. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.

    PubMed

    Vidal, S; Tremblay, M L; Govoni, G; Gauthier, S; Sebastiani, G; Malo, D; Skamene, E; Olivier, M; Jothy, S; Gros, P

    1995-09-01

    In mice, natural resistance or susceptibility to infection with intracellular parasites is determined by a locus or group of loci on chromosome 1, designated Bcg, Lsh, and Ity, which controls early microbial replication in reticuloendothelial organs. We have identified by positional cloning a candidate gene for Bcg, Nramp1, which codes for a novel macrophage-specific membrane transport protein. We have created a mouse mutant bearing a null allele at Nramp1, and we have analyzed the effect of such a mutation on natural resistance to infection. Targeted disruption of Nramp1 has pleiotropic effects on natural resistance to infection with intracellular parasites, as it eliminated resistance to Mycobacterium bovis, Leishmania donovani, and lethal Salmonella typhimurium infection, establishing that Nramp1, Bcg, Lsh, and Ity are the same locus. Comparing the profiles of parasite replication in control and Nramp1-/- mice indicated that the Nramp1Asp169 allele of BcgS inbred strains is a null allele, pointing to a critical role of this residue in the mechanism of action of the protein. Despite their inability to control parasite growth in the early nonimmune phase of the infection, Nramp1-/- mutants can overcome the infection in the late immune phase, suggesting that Nramp1 plays a key role only in the early part of the macrophage-parasite interaction and may function by a cytocidal or cytostatic mechanism distinct from those expressed by activated macrophages.

  16. Genetic factor common to schizophrenia and HIV infection is associated with risky sexual behavior: antagonistic vs. synergistic pleiotropic SNPs enriched for distinctly different biological functions.

    PubMed

    Wang, Qian; Polimanti, Renato; Kranzler, Henry R; Farrer, Lindsay A; Zhao, Hongyu; Gelernter, Joel

    2017-01-01

    Schizophrenia (SZ) and HIV infection are serious disorders with a complex phenotypic relationship. Observational studies have described their comorbidity; their genetic correlation is not well studied. We performed extensive analysis in search of common genetic factors for SZ and HIV, and their relationship with risky sexual behavior (RSB). Summary statistics from genome-wide association studies of HIV infection and schizophrenia were obtained and 2379 European Americans were genotyped and assessed for RSB score. Genetic relationships between traits were analyzed in three ways: linkage disequilibrium (LD) score regression to estimate genetic correlation; GPA (Genetic analysis incorporating Pleiotropy and Annotation) to test pleiotropy and identify pleiotropic loci; polygenic risk scores (PRS) of SZ and HIV to predict RSB using linear regression. We found significant pleiotropy (p = 5.31E - 28) and a positive genetic correlation (cor = 0.17, p = 0.002) for SZ and HIV infection. Pleiotropic SNPs with opposite effect directions (antagonistic) and SNPs with the same effect direction (synergistic) were enriched for distinctly different biological functions. SZ PRS computed with antagonistically pleiotropic SNPs consistently predicted RSB score with nominal significance, but SZ PRS based on either synergistically pleiotropic SNPs or all SNPs did not predict RSB. The epidemiologic correlation between schizophrenia and HIV can partly be explained by overlapping genetic risk factors, which are related to risky sexual behavior.

  17. Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP channels?

    PubMed

    Sehra, Devindra; Sehra, Sudhish; Sehra, Shiv Tej

    2017-07-01

    Statins are considered the main stay of treatment in the prevention of cardio-vascular morbidity and mortality. They have multiple pleiotropic effects, like stabilization of atherosclerotic plaques, inhibition of platelet aggregation, and vascular smooth muscle proliferation; in addition to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels in the cardiac and vascular tissue. Simultaneous activation of the KATP channels by statins in β cells of pancreas may inhibit insulin release which may lead to diabetes. Areas covered: Literature published between 1980 and 2016 on cholesterol biosynthesis, new onset diabetes and on the pleiotropic effects of statins, was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out. Expert opinion: Statins exert their beneficial pleiotropic effects on the cardiovascular system by activating KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels in the beta cells of pancreas leads to inhibition of insulin release. This disturbs the carbohydrate metabolism and probably leads to diabetes. In our opinion, use of stains should be more judicious and restricted to secondary prevention only.

  18. Regulatory effects of genomic translocations at the human carboxylesterase-1 (CES1) gene locus.

    PubMed

    Sanford, Jonathan C; Wang, Xinwen; Shi, Jian; Barrie, Elizabeth S; Wang, Danxin; Zhu, Hao-Jie; Sadee, Wolfgang

    2016-05-01

    CES1 encodes carboxylesterase-1, an important drug-metabolizing enzyme with high expression in the liver. Previous studies have reported a genomic translocation of the 5' region from the poorly expressed pseudogene CES1P1, to CES1, yielding the structural variant CES1VAR. The aim of this study was to characterize this translocation and its effect on CES1 expression in the human liver. Experiments were conducted in human liver tissues and cell culture (HepG2). The promoter and exon 1 of CES1 were sequenced by Sanger and Ion Torrent sequencing to identify gene translocations. The effects of CES1 5'UTRs on mRNA and protein expression were assessed by quantitative real-time PCR, allelic ratio mRNA analysis by primer extension (SNaPshot), quantitative targeted proteomics, and luciferase reporter gene assays. Sequencing of CES1 identified two translocations: first, CES1VAR (17% minor allele frequency) comprising the 5'UTR, exon 1, and part of intron 1. A second shorter translocation, CES1SVAR, was observed excluding exon 1 and intron 1 regions (<0.01% minor allele frequency). CES1VAR is associated with 2.6-fold decreased CES1 mRNA and ∼1.35-fold lower allelic mRNA. Luciferase reporter constructs showed that CES1VAR decreases luciferase activity 1.5-fold, whereas CES1SVAR slightly increases activity. CES1VAR was not associated with CES1 protein expression or metabolism of the CES1 substrates enalapril, clopidogrel, or methylphenidate in the liver. The frequent translocation variant CES1VAR reduces mRNA expression of CES1 in the liver by ∼30%, but protein expression and metabolizing activity in the liver were not detectably altered - possibly because of variable CES1 expression masking small allelic effects. Whether drug therapies are affected by CES1VAR will require further in-vivo studies.

  19. Principles of regulatory information conservation between mouse and human

    SciTech Connect

    Cheng, Yong; Ma, Zhihai; Kim, Bong-Hyun; Wu, Weisheng; Cayting, Philip; Boyle, Alan P.; Sundaram, Vasavi; Xing, Xiaoyun; Dogan, Nergiz; Li, Jingjing; Euskirchen, Ghia; Lin, Shin; Lin, Yiing; Visel, Axel; Kawli, Trupti; Yang, Xinqiong; Patacsil, Dorrelyn; Keller, Cheryl A.; Giardine, Belinda; Kundaje, Anshul; Wang, Ting; Pennacchio, Len A.; Weng, Zhiping; Hardison, Ross C.; Snyder, Michael P.

    2014-11-19

    To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human–mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Lastly, single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.

  20. Principles of regulatory information conservation between mouse and human

    DOE PAGES

    Cheng, Yong; Ma, Zhihai; Kim, Bong-Hyun; ...

    2014-11-19

    To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human–mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and withmore » genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Lastly, single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.« less

  1. Principles Of Regulatory Information Conservation Between Mouse And Human

    PubMed Central

    Kim, Bong-Hyun; Wu, Weisheng; Cayting, Philip; Boyle, Alan P.; Sundaram, Vasavi; Xing, Xiaoyun; Dogan, Nergiz; Li, Jingjing; Euskirchen, Ghia; Lin, Shin; Lin, Yiing; Visel, Axel; Kawli, Trupti; Yang, Xinqiong; Patacsil, Dorrelyn; Keller, Cheryl A.; Giardine, Belinda; Kundaje, Anshul; Wang, Ting; Pennacchio, Len A.; Weng, Zhiping; Hardison, Ross C.; Snyder, Michael P.

    2015-01-01

    Summary To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast, and embryonic stem cell lines. By combining the genome-wide TF occupancy repertoires, associated epigenetic signals, and TF co-association patterns, we deduced several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF occupied sequences (TF OSs). However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Importantly, occupancy conserved TF OSs tend to be pleiotropic; they function in multiple tissues and also co-associate with multiple TFs. Single nucleotide variants (SNVs) at sites with potential regulatory functions are enriched in occupancy conserved TF OSs. PMID:25409826

  2. Principles of regulatory information conservation between mouse and human.

    PubMed

    Cheng, Yong; Ma, Zhihai; Kim, Bong-Hyun; Wu, Weisheng; Cayting, Philip; Boyle, Alan P; Sundaram, Vasavi; Xing, Xiaoyun; Dogan, Nergiz; Li, Jingjing; Euskirchen, Ghia; Lin, Shin; Lin, Yiing; Visel, Axel; Kawli, Trupti; Yang, Xinqiong; Patacsil, Dorrelyn; Keller, Cheryl A; Giardine, Belinda; Kundaje, Anshul; Wang, Ting; Pennacchio, Len A; Weng, Zhiping; Hardison, Ross C; Snyder, Michael P

    2014-11-20

    To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.

  3. Genetic relationship between lodging and lodging components in barley (Hordeum vulgare) based on unconditional and conditional quantitative trait locus analyses.

    PubMed

    Chen, W Y; Liu, Z M; Deng, G B; Pan, Z F; Liang, J J; Zeng, X Q; Tashi, N M; Long, H; Yu, M Q

    2014-03-17

    Lodging (LD) is a major constraint limiting the yield and forage quality of barley. Detailed analyses of LD component (LDC) traits were conducted using 246 F2 plants generated from a cross between cultivars ZQ320 and 1277. Genetic relationships between LD and LDC were evaluated by unconditional and conditional quantitative trait locus (QTL) mapping with 117 simple sequence repeat markers. Ultimately, 53 unconditional QTL related to LD were identified on seven barley chromosomes. Up to 15 QTL accounted for over 10% of the phenotypic variation, and up to 20 QTL for culm strength were detected. Six QTL with pleiotropic effects showing significant negative correlations with LD were found between markers Bmag353 and GBM1482 on chromosome 4H. These alleles and alleles of QTL for wall thickness, culm strength, plant height, and plant weight originated from ZQ320. Conditional mapping identified 96 additional QTL for LD. Conditional QTL analysis demonstrated that plant height, plant height center of gravity, and length of the sixth internode had the greatest contribution to LD, whereas culm strength and length of the fourth internode, and culm strength of the second internode were the key factors for LD-resistant. Therefore, lodging resistance in barley can be improved based on selection of alleles affecting culm strength, wall thickness, plant height, and plant weight. The conditional QTL mapping method can be used to evaluate possible genetic relationships between LD and LDC while efficiently and precisely determining counteracting QTL, which will help in understanding the genetic basis of LD in barley.

  4. GIGANTEA directly activates Flowering Locus T in Arabidopsis thaliana

    PubMed Central

    Sawa, Mariko; Kay, Steve A.

    2011-01-01

    Plants perceive environmental signals such as day length and temperature to determine optimal timing for the transition from vegetative to floral stages. Arabidopsis flowers under long-day conditions through the CONSTANS (CO)–FLOWERING LOCUS T (FT) regulatory module. It is thought that the environmental cues for photoperiodic control of flowering are initially perceived in the leaves. We have previously shown that GIGANTEA (GI) regulates the timing of CO expression, together with FLAVIN-BINDING, KELCH REPEAT, F BOX protein 1. Normally, CO and FT are expressed exclusively in vascular bundles, whereas GI is expressed in various tissues. To better elucidate the role of tissue-specific expression of GI in the flowering pathway, we established transgenic lines in which GI is expressed exclusively in mesophyll, vascular bundles, epidermis, shoot apical meristem, or root. We found that GI expressed in either mesophyll or vascular bundles rescues the late-flowering phenotype of the gi-2 loss-of-function mutant under both short-day and long-day conditions. Interestingly, GI expressed in mesophyll or vascular tissues increases FT expression without up-regulating CO expression under short-day conditions. Furthermore, we examined the interaction between GI and FT repressors in mesophyll. We found that GI can bind to three FT repressors: SHORT VEGETATIVE PHASE (SVP), TEMPRANILLO (TEM)1, and TEM2. Finally, our chromatin immunoprecipitation experiments showed that GI binds to FT promoter regions that are near the SVP binding sites. Taken together, our data further elucidate the multiple roles of GI in the regulation of flowering time. PMID:21709243

  5. Regulatory guidance document

    SciTech Connect

    1994-05-01

    The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM`s evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7.

  6. Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

    PubMed Central

    Valle-Mendiola, Arturo; Gutiérrez-Hoya, Adriana; Lagunas-Cruz, María del Carmen; Weiss-Steider, Benny; Soto-Cruz, Isabel

    2016-01-01

    IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow. PMID:27293315

  7. Blocking histone deacetylation in Arabidopsis induces pleiotropic effects on plant gene regulation and development

    PubMed Central

    Tian, Lu; Chen, Z. Jeffrey

    2001-01-01

    Histone acetylation and deacetylation play essential roles in eukaryotic gene regulation. Reversible modifications of core histones are catalyzed by two intrinsic enzymes, histone acetyltransferase and histone deacetylase (HD). In general, histone deacetylation is related to transcriptional gene silencing, whereas acetylation correlates with gene activation. We produced transgenic plants expressing the antisense Arabidopsis HD (AtHD1) gene. AtHD1 is a homolog of human HD1 and RPD3 global transcriptional regulator in yeast. Expression of the antisense AtHD1 caused dramatic reduction in endogenous AtHD1 transcription, resulting in accumulation of acetylated histones, notably tetraacetylated H4. Reduction in AtHD1 expression and AtHD1 production and changes in acetylation profiles were associated with various developmental abnormalities, including early senescence, ectopic expression of silenced genes, suppression of apical dominance, homeotic changes, heterochronic shift toward juvenility, flower defects, and male and female sterility. Some of the phenotypes could be attributed to ectopic expression of tissue-specific genes (e.g., SUPERMAN) in vegetative tissues. No changes in genomic DNA methylation were detected in the transgenic plants. These results suggest that AtHD1 is a global regulator, which controls gene expression during development through DNA-sequence independent or epigenetic mechanisms in plants. In addition to DNA methylation, histone modifications may be involved in a general regulatory mechanism responsible for plant plasticity and variation in nature. PMID:11134508

  8. Locus of Control and Death Anxiety: A Reexamination.

    ERIC Educational Resources Information Center

    Sadowski, Cyril J.; And Others

    1979-01-01

    Examined the relationship between locus of control and death anxiety. The Reid-Ware Three Factor Locus of Control Scale and Templer Death Anxiety Scale were administered to college students aged 17 to 49. Death anxiety loaded significantly on the Fatalism dimension for males and on the Social System Control dimension for females. (Author/BWF)

  9. Metacognition: As a Predictor of One's Academic Locus of Control

    ERIC Educational Resources Information Center

    Arslan, Serhat; Akin, Ahmet

    2014-01-01

    The purpose of this study is to examine the effect of metacognition on one's academic locus of control. The study's sample group consists of 451 university students enrolled in various programs at Sakarya University, Turkey. In this study, the Metacognitive Awareness Inventory and the Academic Locus of Control Scale were used. The correlations and…

  10. Anxiety, locus of control and appraisal of air pollution

    SciTech Connect

    Navarro, P.L.; Simpson-Housley, P.; de Man, A.F.

    1987-06-01

    100 residents of Santiago de Chile took part in a study of the relationship among locus of control, trait-anxiety, and perception of air pollution. Concern over the problem of atmospheric pollution and number of antipollution measures taken was related to trait-anxiety. Locus of control was associated with variation in awareness of pollution hazard.

  11. Personality and Locus of Control among School Children

    ERIC Educational Resources Information Center

    Pandya, Archana A.; Jogsan, Yogesh A.

    2013-01-01

    The main purpose of this investigation is to find out the sex differences in personality traits and locus of control among school children. A total 60 children (30 boys and 30 girls) were taken as a sample. The research tool for personality, children personality questionnaire was used, which was made by Cattell and Porter. Locus of control was…

  12. Personality and Locus of Control among School Children

    ERIC Educational Resources Information Center

    Pandya, Archana A.; Jogsan, Yogesh A.

    2013-01-01

    The main purpose of this investigation is to find out the sex differences in personality traits and locus of control among school children. A total 60 children (30 boys and 30 girls) were taken as a sample. The research tool for personality, children personality questionnaire was used, which was made by Cattell and Porter. Locus of control was…

  13. The Locus of Control Construct in EEG Alpha Rhythm Feedback

    ERIC Educational Resources Information Center

    Johnson, Richard K.; Meyer, Robert G.

    1974-01-01

    The present study investigated locus of control, and performance in a biofeedback situation where the goal was to increase EEG alpha rhythm. Subjects with an internal locus of control were better able to use feedback to increase their alpha activity than external subjects. (Author)

  14. Acculturation and Health Locus of Control among Mexican American Adolescents.

    ERIC Educational Resources Information Center

    Guinn, Bobby

    1998-01-01

    Health locus of control was investigated across culture of origin (Mexicanism), mainstream culture (Americanism), and bicultural linguistic-acculturation domains among 424 Mexican-American adolescents. Belief in powerful others' external control was the strongest explanation of locus of control in the culture-of-origin domain; internal control was…

  15. Physical Attractiveness, Locus of Control, Sex Role, and Conversational Assertiveness.

    ERIC Educational Resources Information Center

    Campbell, Keith F.; And Others

    1990-01-01

    Analyzes the relationship among physical attractiveness, locus of control, sex role orientation, and assertiveness in undergraduate students. Reviews videotapes of mixed-sex student groups engaged in discussion. Finds an internal locus of control positively correlated with assertiveness. Uses a behavioral measure of assertiveness rather than…

  16. Locus of Control in Underachieving and Achieving Gifted Students.

    ERIC Educational Resources Information Center

    McClelland, Robert; And Others

    1991-01-01

    This study, with 87 underachieving and 77 achieving gifted students in grades 6-9, found that general locus of control measures did not differentiate between the 2 groups, that both scored significantly higher on positive internal than on negative internal locus of control, and that there were no gender or grade effects. (Author/DB)

  17. Externality and Locus of Control in Obese Children.

    ERIC Educational Resources Information Center

    Isbitsky, Joyce Renee; White, Donna Romano

    1981-01-01

    Significant sex differences indicated that boys generally ate more than girls and held more internal locus of control expectancies. However, obese and normal-weighted children were not differentiated by their performance on either food-related measures nor by their locus of control expectancies. (Author/MP)

  18. The Cajal Body and Histone Locus Body

    PubMed Central

    Nizami, Zehra; Deryusheva, Svetlana; Gall, Joseph G.

    2010-01-01

    The Cajal body (CB) is a nuclear organelle present in all eukaryotes that have been carefully studied. It is identified by the signature protein coilin and by CB-specific RNAs (scaRNAs). CBs contain high concentrations of splicing small nuclear ribonucleoproteins (snRNPs) and other RNA processing factors, suggesting that they are sites for assembly and/or posttranscriptional modification of the splicing machinery of the nucleus. The histone locus body (HLB) contains factors required for processing histone pre-mRNAs. As its name implies, the HLB is associated with the genes that code for histones, suggesting that it may function to concentrate processing factors at their site of action. CBs and HLBs are present throughout the interphase of the cell cycle, but disappear during mitosis. The biogenesis of CBs shows the features of a self-organizing structure. PMID:20504965

  19. Identifying a novel locus for psoriatic arthritis

    PubMed Central

    Budu-Aggrey, Ashley; Bowes, John

    2016-01-01

    A number of studies have identified genetic risk loci for PsA, the majority of which also confer risk for psoriasis. The stronger heritability of PsA in comparison with psoriasis suggests that there should be risk loci that are specific for PsA. Identifying such loci could potentially inform therapy development to provide more effective treatments for PsA patients, especially with a considerable proportion being non-responsive to current therapies. Evidence of a PsA-specific locus has been previously found at HLA-B27 within the MHC region. A recent study has provided evidence of non-HLA risk loci that are specific for PsA at IL23R, PTPN22 and on chromosome 5q31. Functional characterization of these loci will provide further understanding of the pathways underlying PsA, and enable us to apply genetic findings for patient benefit. PMID:26255310

  20. Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells.

    PubMed

    López Rodríguez, Maykel; Kaminska, Dorota; Lappalainen, Kati; Pihlajamäki, Jussi; Kaikkonen, Minna U; Laakso, Markku

    2017-07-06

    Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094. We used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies. The ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver. Our results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by

  1. 3 CFR - Regulatory Review

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... in general—should be revisited. I therefore direct the Director of OMB, in consultation with... delay; clarify the role of the behavioral sciences in formulating regulatory policy; and identify...

  2. Select Biosolids Regulatory Processes

    EPA Pesticide Factsheets

    Historical Regulatory Development and activities EPA has undertaken to respond to statutory obligations, respond to the National Academy of Sciences, understand pollutants that may occur in sewage sludge, and address dioxins in sewage sludge.

  3. Regulatory T cell memory

    PubMed Central

    Rosenblum, Michael D.; Way, Sing Sing; Abbas, Abul K.

    2016-01-01

    Memory for antigen is a defining feature of adaptive immunity. Antigen-specific lymphocyte populations show an increase in number and function after antigen encounter and more rapidly re-expand upon subsequent antigen exposure. Studies of immune memory have primarily focused on effector B cells and T cells with microbial specificity, using prime challenge models of infection. However, recent work has also identified persistently expanded populations of antigen-specific regulatory T cells that protect against aberrant immune responses. In this Review, we consider the parallels between memory effector T cells and memory regulatory T cells, along with the functional implications of regulatory memory in autoimmunity, antimicrobial host defence and maternal fetal tolerance. In addition, we discuss emerging evidence for regulatory T cell memory in humans and key unanswered questions in this rapidly evolving field. PMID:26688349

  4. Effects of preferred retinal locus placement on text navigation and development of advantageous trained retinal locus.

    PubMed

    Watson, Gale R; Schuchard, Ronald A; De l'Aune, William R; Watkins, Erica

    2006-01-01

    Sixty readers were evaluated for visual function and text-navigation ability. The visual field and preferred retinal locus (PRL) were measured with a scanning laser ophthalmoscope (SLO). We found significant differences in text-navigation ability based on scotoma and PRL placement. Readers with a PRL to the left of or above a scotoma had significantly less text-navigation abilities. Readers with a PRL to the left of a scotoma tended to misread words with similar beginnings and omit the last word on a line. Readers with a PRL above a scotoma tended to skip a line or reread the same line twice. In a follow-up study, seven subjects with a nonadvantageous PRL quickly developed a trained retinal locus (TRL) during instruction with an SLO. Although the readers developed the TRL in about 15 minutes, they read slower with the TRL than the PRL. This TRL research provides promising pilot data.

  5. Assessing the regulatory picture

    SciTech Connect

    Not Available

    1994-02-01

    This article addresses the safety of the nation's drinking water supply and discusses compliance of the Clean Water Act. Right now, the shape of the regulatory future is uncertain. The results of the D-DBP regulatory negotiation are imminent. Congress is ready to begin debating reauthorization of the Safe Drinking Water Act, and utilities are trying to comply with the regulations while trying not to price water out of the reach of some of their customers.

  6. NRC regulatory initiatives

    SciTech Connect

    Johnson, T.C.

    1989-11-01

    The US Nuclear Regulatory Commission (NRC) is addressing several low-level waste disposal issues that will be important to waste generators and to States and Compacts developing new disposal capacity. These issues include Greater-Than-Class C (GTCC) waste, mixed waste, below regulatory concern (BRC) waste, and the low-level waste data base. This paper discusses these issues and their current status.

  7. Locus of Control Orientation: Parents, Peers, and Place.

    PubMed

    Ahlin, Eileen M; Lobo Antunes, Maria João

    2015-09-01

    An internal locus of control contributes to positive youth outcomes such as a general well-being and academic success, while also serving as a protective factor against exposure to community violence and reducing negative behaviors like violence. Despite these benefits, very little is known about antecedents of an internal locus of control orientation. Without an understanding of what factors contribute to the development of an internal locus of control, it is not clear how to best encourage its formation. This study uses data from the Project on Human Development in Chicago Neighborhoods to examine whether various mesosystem variables (family management strategies, peer interactions, neighborhood context, and individual-level characteristics) are associated with an internal locus of control orientation among 1,076 youth ages 9-19 living in 78 Chicago neighborhoods. Study participants were Hispanic (46 %), African American (34 %), and White (15 %), and 50 % were female. The findings suggest that, while most levels of the mesosystem influence locus of control orientation, family management strategies are more prominent determinants of an internal locus of control than peers, neighborhood context, or individual characteristics. Parental supervision over the time a youth spends at home and family socioeconomic status are consistent predictors of an internal locus of control, while harsh discipline is associated with an external locus of control. The discussion examines the import of various parenting techniques in shaping an internal locus of control and considers future avenues for research to further unpack how antecedents of locus of control can vary across youth.

  8. Allelic Variation within the Emv-15 Locus Defines Genomic Sequences Closely Linked to the agouti Locus on Mouse Chromosome 2

    PubMed Central

    Siracusa, Linda D.; Russell, Liane B.; Jenkins, Nancy A.; Copeland, Neal G.

    1987-01-01

    Gene(s) at the agouti locus act within the microenvironment of the hair follicle to switch pigment synthesis in the melanocyte between eumelanin (black or brown pigment) and phaeomelanin (yellow pigment). Many phenotypic variants of this locus have been described. The mechanism(s) of gene action causing such variation in coat-color phenotype is not known. The close linkage of an endogenous ecotropic murine leukemia provirus, Emv-15 , to the lethal yellow mutation of the agouti locus provides a means to molecularly access genes at or near the agouti locus. We have identified and used a unique mouse sequence flanking the Emv-15 provirus to define three alleles of the Emv-15 locus. We found a correlation between the presence of specific Emv-15 alleles and the origins of specific agouti locus mutations, confirming close linkage. However, we found some exceptions which suggest that the Emv-15 locus is closely linked to, but genetically separable from, the agouti locus. PMID:2822532

  9. [Regulatory T cells].

    PubMed

    Marinić, Igor; Gagro, Alenka; Rabatić, Sabina

    2006-12-01

    Regulatory T-cells are a subset of T cells that have beene extensively studied in modern immunology. They are important for the maintenance of peripheral tolerance, and have an important role in various clinical conditions such as allergy, autoimmune disorders, tumors, infections, and in transplant medicine. Basically, this population has a suppressive effect on the neighboring immune cells, thus contributing to the local modulation and control of immune response. There are two main populations of regulatory T cells - natural regulatory T cells, which form a distinct cellular lineage, develop in thymus and perform their modulatory action through direct intercellular contact, along with the secreted cytokines; and inducible regulatory T cells, which develop in the periphery after contact with the antigen that is presented on the antigen presenting cell, and their primary mode of action is through the interleukin 10 (IL-10) and transforming growth factor beta (TGF-alpha) cytokines. Natural regulatory T cells are activated through T cell receptor after contact with specific antigen and inhibit proliferation of other T cells in an antigen independent manner. One of the major difficulties in the research of regulatory T cells is the lack of specific molecular markers that would identify these cells. Natural regulatory T cells constitutively express surface molecule CD25, but many other surface and intracellular molecules (HLA-DR, CD122, CD45RO, CD62, CTLA-4, GITR, PD-1, Notch, FOXP3, etc.) are being investigated for further phenotypic characterization of these cells. Because regulatory T cells have an important role in establishing peripheral tolerance, their importance is manifested in a number of clinical conditions. In the IPEX syndrome (immunodysregulation, polyendocrinopathy and enteropathy, X-linked), which is caused by mutation in Foxp3 gene that influences the development and function of regulatory T cells, patients develop severe autoimmune reactions that

  10. Genome-wide quantitative trait locus mapping identifies multiple major loci for brittle rachis and threshability in Tibetan semi-wild wheat (Triticum aestivum ssp. tibetanum Shao).

    PubMed

    Jiang, Yun-Feng; Lan, Xiu-Jin; Luo, Wei; Kong, Xing-Chen; Qi, Peng-Fei; Wang, Ji-Rui; Wei, Yu-Ming; Jiang, Qian-Tao; Liu, Ya-Xi; Peng, Yuan-Ying; Chen, Guo-Yue; Dai, Shou-Fen; Zheng, You-Liang

    2014-01-01

    Tibetan semi-wild wheat (Triticum aestivum ssp. tibetanum Shao) is a semi-wild hexaploid wheat resource that is only naturally distributed in the Qinghai-Tibet Plateau. Brittle rachis and hard threshing are two important characters of Tibetan semi-wild wheat. A whole-genome linkage map of T. aestivum ssp. tibetanum was constructed using a recombinant inbred line population (Q1028×ZM9023) with 186 lines, 564 diversity array technology markers, and 117 simple sequence repeat markers. Phenotypic data on brittle rachis and threshability, as two quantitative traits, were evaluated on the basis of the number of average spike rachis fragments per spike and percent threshability in 2012 and 2013, respectively. Quantitative trait locus (QTL) mapping performed using inclusive composite interval mapping analysis clearly identified four QTLs for brittle rachis and three QTLs for threshability. However, three loci on 2DS, 2DL, and 5AL showed pleiotropism for brittle rachis and threshability; they respectively explained 5.3%, 18.6%, and 18.6% of phenotypic variation for brittle rachis and 17.4%, 13.2%, and 35.2% of phenotypic variation for threshability. A locus on 3DS showed an independent effect on brittle rachis, which explained 38.7% of the phenotypic variation. The loci on 2DS and 3DS probably represented the effect of Tg and Br1, respectively. The locus on 5AL was in very close proximity to the Q gene, but was different from the predicted q in Tibetan semi-wild wheat. To our knowledge, the locus on 2DL has never been reported in common wheat but was prominent in T. aestivum ssp. tibetanum accession Q1028. It remarkably interacted with the locus on 5AL to affect brittle rachis. Several major loci for brittle rachis and threshability were identified in Tibetan semi-wild wheat, improving the understanding of these two characters and suggesting the occurrence of special evolution in Tibetan semi-wild wheat.

  11. Low Cost Upper Atmosphere Sounder (LOCUS)

    NASA Astrophysics Data System (ADS)

    Gerber, Daniel; Swinyard, Bruce M.; Ellison, Brian N.; Aylward, Alan D.; Aruliah, Anasuya; Plane, John M. C.; Feng, Wuhu; Saunders, Christopher; Friend, Jonathan; Bird, Rachel; Linfield, Edmund H.; Davies, A. Giles; Parkes, Steve

    2014-05-01

    near future. We describe the current instrument configuration of LOCUS, and give a first preview of the expected science return such a mission would yield. The LOCUS instrument concept calls for four spectral bands, a first band at 4.7 THz to target atomic oxygen (O), a second band at 3.5 THz to target hydroxyl (OH), a third band at 1.1 THz to cover several diatomic species (NO, CO, O3, H2O) and finally a fourth band at 0.8 THz to retrieve pointing information from molecular oxygen (O2). LOCUS would be the first satellite instrument to measure atomic oxygen on a global scale with a precision that will allow the retrieval of the global O distribution. It would also be the first time that annual and diurnal changes in O are measured. This will be a significant step forward in understanding the chemistry and dynamics of the MLT. Current indications (derived from CRISTA measurement) lead us to believe that current models only give a poor representation of upper atmospheric O. The secondary target species can help us to address additional scientific questions related to both Climate (distribution of climate relevant gases, highly geared cooling of the MLT in response to Climate change, increased occurrence of Polar Mesospheric Clouds (PMC), etc) and Space Weather (precipitation of electrically charged particles and impact on NOx chemistry, fluctuations of solar Lyman-alpha flux through shown in the the distribution of photochemically active species, etc).

  12. AKT as locus of fragility in robust cancer system.

    PubMed

    Radisavljevic, Ziv

    2008-08-15

    Metastatic cancer is a complex positive feedback loop system. Such as system has a tendency to acquire extreme robustness. Signaling pathways controlling that robustness can fail completely if an essential element from the signaling is removed. That element is a locus of fragility. Targeting that locus represents the best way to target the cancer robustness. This prospect presents another locus of fragility in signaling complex system network, controlling the cell cycle progression through the PI3K/AKT/mTOR/RAN pathway and cell migration and angiogenesis through the VEGF/PI3K/AKT/NO/ICAM-1 pathway. The locus of fragility of these pathways is AKT, which is regulated by a balance of catalase/H2O2 or by AKT inhibitor. Tiny and trivial perturbations such as change in redox state in the cells by antioxidant enzyme catalase, scavenging H2O2 signaling molecule, regulates robust signaling molecule AKT, abolishing its phosporilation and inducing cascading failure of robust signaling pathways for cell growth, proliferation, migration, and angiogenesis. An anticancer effect of the antioxidant is achieved through the AKT locus, by abolishing signals from growth factors VEGF, HGF, HIF-1alpha and H2O2. Previously reported locus of fragility nitric oxide (NO) and locus AKT are close in the complex signaling interactome network, but they regulate distinct signaling modules. Simultaneously targeted loci represents new principles in cancer robustness chemotherapy by blocking cell proliferation, migration, angiogenesis and inducing rather slow then fast apoptosis leading to slow eradication of cancer.

  13. Detecting purely epistatic multi-locus interactions by an omnibus permutation test on ensembles of two-locus analyses

    PubMed Central

    Wongseree, Waranyu; Assawamakin, Anunchai; Piroonratana, Theera; Sinsomros, Saravudh; Limwongse, Chanin; Chaiyaratana, Nachol

    2009-01-01

    Background Purely epistatic multi-locus interactions cannot generally be detected via single-locus analysis in case-control studies of complex diseases. Recently, many two-locus and multi-locus analysis techniques have been shown to be promising for the epistasis detection. However, exhaustive multi-locus analysis requires prohibitively large computational efforts when problems involve large-scale or genome-wide data. Furthermore, there is no explicit proof that a combination of multiple two-locus analyses can lead to the correct identification of multi-locus interactions. Results The proposed 2LOmb algorithm performs an omnibus permutation test on ensembles of two-locus analyses. The algorithm consists of four main steps: two-locus analysis, a permutation test, global p-value determination and a progressive search for the best ensemble. 2LOmb is benchmarked against an exhaustive two-locus analysis technique, a set association approach, a correlation-based feature selection (CFS) technique and a tuned ReliefF (TuRF) technique. The simulation results indicate that 2LOmb produces a low false-positive error. Moreover, 2LOmb has the best performance in terms of an ability to identify all causative single nucleotide polymorphisms (SNPs) and a low number of output SNPs in purely epistatic two-, three- and four-locus interaction problems. The interaction models constructed from the 2LOmb outputs via a multifactor dimensionality reduction (MDR) method are also included for the confirmation of epistasis detection. 2LOmb is subsequently applied to a type 2 diabetes mellitus (T2D) data set, which is obtained as a part of the UK genome-wide genetic epidemiology study by the Wellcome Trust Case Control Consortium (WTCCC). After primarily screening for SNPs that locate within or near 372 candidate genes and exhibit no marginal single-locus effects, the T2D data set is reduced to 7,065 SNPs from 370 genes. The 2LOmb search in the reduced T2D data reveals that four intronic SNPs

  14. No Excess of Cis-Regulatory Variation Associated with Intraspecific Selection in Wild Pearl Millet (Cenchrus americanus)

    PubMed Central

    Rhoné, Bénédicte; Mariac, Cédric; Couderc, Marie; Berthouly-Salazar, Cécile; Ousseini, Issaka Salia

    2017-01-01

    Several studies suggest that cis-regulatory mutations are the favorite target of evolutionary changes, one reason being that cis-regulatory mutations might have fewer deleterious pleiotropic effects than protein-coding mutations. A review of the process also suggests that this bias towards adaptive cis-regulatory variation might be less pronounced at the intraspecific level compared with the interspecific level. In this study, we assessed the contribution of cis-regulatory variation to adaptation at the intraspecific level using populations of wild pearl millet (Cenchrus americanus ssp. monodii) sampled along an environmental gradient in Niger. From RNA sequencing of hybrids to assess allele-specific expression, we identified genes with cis-regulatory divergence between two parental accessions collected in contrasted environmental conditions. This revealed that ∼15% of transcribed genes showed cis-regulatory variation. Intersecting the gene set exhibiting cis-regulatory variation with the gene set identified as targets of selection revealed no excess of cis-acting mutations among the selected genes. We additionally found no excess of cis-regulatory variation among genes associated with adaptive traits. As our approach relied on methods identifying mainly genes submitted to strong selection pressure or with high phenotypic effect, the contribution of cis-regulatory changes to soft selection or polygenic adaptive traits remains to be tested. However our results favor the hypothesis that enrichment of adaptive cis-regulatory divergence builds up over time. For short evolutionary time-scales, cis-acting mutations are not predominantly involved in adaptive evolution associated with strong selective signal. PMID:28137746

  15. Unusual Regulation of Splicing of the Cholinergic Locus in Caenorhabditis elegans

    PubMed Central

    Mathews, Eleanor A.; Mullen, Gregory P.; Manjarrez, Jacob R.; Rand, James B.

    2015-01-01

    The essential neurotransmitter acetylcholine functions throughout the animal kingdom. In Caenorhabditis elegans, the acetylcholine biosynthetic enzyme [choline acetyltransferase (ChAT)] and vesicular transporter [vesicular acetylcholine transporter (VAChT)] are encoded by the cha-1 and unc-17 genes, respectively. These two genes compose a single complex locus in which the unc-17 gene is nested within the first intron of cha-1, and the two gene products arise from a common pre-messenger RNA (pre-mRNA) by alternative splicing. This genomic organization, known as the cholinergic gene locus (CGL), is conserved throughout the animal kingdom, suggesting that the structure is important for the regulation and function of these genes. However, very little is known about CGL regulation in any species. We now report the identification of an unusual type of splicing regulation in the CGL of C. elegans, mediated by two pairs of complementary sequence elements within the locus. We show that both pairs of elements are required for efficient splicing to the distal acceptor, and we also demonstrate that proper distal splicing depends more on sequence complementarity within each pair of elements than on the sequences themselves. We propose that these sequence elements are able to form stem-loop structures in the pre-mRNA; such structures would favor specific splicing alternatives and thus regulate CGL splicing. We have identified complementary elements at comparable locations in the genomes of representative species of other animal phyla; we suggest that this unusual regulatory mechanism may be a general feature of CGLs. PMID:25571900

  16. Bacillus anthracis sin Locus and Regulation of Secreted Proteases ▿ †

    PubMed Central

    Pflughoeft, Kathryn J.; Sumby, Paul; Koehler, Theresa M.

    2011-01-01

    Bacillus anthracis shares many regulatory loci with the nonpathogenic Bacillus species Bacillus subtilis. One such locus is sinIR, which in B. subtilis controls sporulation, biofilm formation, motility, and competency. As B. anthracis is not known to be motile, to be naturally competent, or to readily form biofilms, we hypothesized that the B. anthracis sinIR regulon is distinct from that of B. subtilis. A genome-wide expression microarray analysis of B. anthracis parental and sinR mutant strains indicated limited convergence of the B. anthracis and B. subtilis SinR regulons. The B. anthracis regulon includes homologues of some B. subtilis SinR-regulated genes, including the signal peptidase gene sipW near the sinIR locus and the sporulation gene spoIIE. The B. anthracis SinR protein also negatively regulates transcription of genes adjacent to the sinIR locus that are unique to the Bacillus cereus group species. These include calY and inhA1, structural genes for the metalloproteases camelysin and immune inhibitor A1 (InhA1), which have been suggested to be associated with virulence in B. cereus and B. anthracis, respectively. Electrophoretic mobility shift assays revealed direct binding of B. anthracis SinR to promoter DNA from strongly regulated genes, such as calY and sipW, but not to the weakly regulated inhA1 gene. Assessment of camelysin and InhA1 levels in culture supernates from sinR-, inhA1-, and calY-null mutants showed that the concentration of InhA1 in the culture supernatant is inversely proportional to the concentration of camelysin. Our data are consistent with a model in which InhA1 protease levels are controlled at the transcriptional level by SinR and at the posttranslational level by camelysin. PMID:21131488

  17. The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.

    PubMed

    Shore, Robert; Covill, Laura; Pettigrew, Kerry A; Brandler, William M; Diaz, Rebeca; Xu, Yiwang; Tello, Javier A; Talcott, Joel B; Newbury, Dianne F; Stein, John; Monaco, Anthony P; Paracchini, Silvia

    2016-05-01

    We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.

  18. The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

    PubMed Central

    Shore, Robert; Covill, Laura; Pettigrew, Kerry A.; Brandler, William M.; Diaz, Rebeca; Xu, Yiwang; Tello, Javier A.; Talcott, Joel B.; Newbury, Dianne F.; Stein, John; Monaco, Anthony P.; Paracchini, Silvia

    2016-01-01

    We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10−8) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left–right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation. PMID:26908617

  19. AKT as locus of cancer multidrug resistance and fragility.

    PubMed

    Radisavljevic, Ziv

    2013-04-01

    Complexity and robustness of cancer hypoxic microenvironment are supported by the robust signaling networks of autocrine and paracrine elements creating powerful interactome for multidrug resistance. These elements generate a positive feedback loops responsible for the extreme robustness and multidrug resistance in solid cancer, leukemia, myeloma, and lymphoma. Phosphorylated AKT is a cancer multidrug resistance locus. Targeting that locus by oxidant/antioxidant balance modulation, positive feedback loops are converted into negative feedback loops, leading to disappearance of multidrug resistance. This is a new principle for targeting cancer multidrug resistance by the locus chemotherapy inducing a phenomenon of loops conversion. Copyright © 2012 Wiley Periodicals, Inc.

  20. Relation of organizational citizenship behavior and locus of control.

    PubMed

    Turnipseed, David L; Bacon, Calvin M

    2009-12-01

    The relation of organizational citizenship behavior and locus of control was assessed in a sample of 286 college students (52% men; M age = 24 yr.) who worked an average of 26 hr. per week. Measures were Spector's Work Locus of Control Scale and Podsakoff, et al.'s Organization Citizenship Behavior scale. Hierarchical multiple regressions indicated positive association of scores on work locus of control with scores on each of the four tested dimensions of organizational citizenship, as well as total organizational citizenship behavior.

  1. Fine-structure genetic map of the cysB locus in Salmonella typhimurium.

    PubMed Central

    Cheney, R W; Kredich, N M

    1975-01-01

    A genetic map of the cysB region of the Salmonella typhimurium chromosome was constructed using bacteriophage P22-mediated transduction. Strains bearing delta (supX cysB) mutations were employed to divide this regulatory locus into 12 segments containing a total of 39 single-site mutations. Twenty-five of these single-site mutations were further ordered by reciprocal three-point crosses. The results do not support the concept of multiple cistrons at cysB and suggest that the abortive transductants previously observed in crosses between certain cysB mutants were due to intracistronic complementation. The prototrophic cys-1352 mutation, which causes the constitutive expression of the cysteine biosynthetic enzymes, was found to lie within the cysB region itself. It is bracketed by mutations, which lead to an inability to derepress for these enzymes and result in auxotrophy for cysteine. PMID:1104581

  2. Genetic analysis of absB, a Streptomyces coelicolor locus involved in global antibiotic regulation.

    PubMed

    Adamidis, T; Champness, W

    1992-07-01

    The filamentous soil bacterium Streptomyces coelicolor is known to produce four antibiotics which are genetically and structurally distinct. An extensive search for antibiotic regulatory mutants led to the discovery of absB mutants, which are antibiotic deficient but sporulation proficient. Genetic analysis of the absB mutants has resulted in definition of the absB locus at 5 o'clock on the genetic map. Multiple cloned copies of the actII-ORF4 gene, an activator of synthesis of the antibiotic actinorhodin, restore actinorhodin biosynthetic capability to the absB mutants. These results are interpreted to mean that the failure of absB mutants to produce antibiotics results from decreased expression of the antibiotic genes. The absB gene is proposed to be involved in global regulation of antibiotic synthesis.

  3. A single locus confers tolerance to continuous light and allows substantial yield increase in tomato.

    PubMed

    Velez-Ramirez, Aaron I; van Ieperen, Wim; Vreugdenhil, Dick; van Poppel, Pieter M J A; Heuvelink, Ep; Millenaar, Frank F

    2014-08-05

    An important constraint for plant biomass production is the natural day length. Artificial light allows for longer photoperiods, but tomato plants develop a detrimental leaf injury when grown under continuous light--a still poorly understood phenomenon discovered in the 1920s. Here, we report a dominant locus on chromosome 7 of wild tomato species that confers continuous light tolerance. Genetic evidence, RNAseq data, silencing experiments and sequence analysis all point to the type III light harvesting chlorophyll a/b binding protein 13 (CAB-13) gene as a major factor responsible for the tolerance. In Arabidopsis thaliana, this protein is thought to have a regulatory role balancing light harvesting by photosystems I and II. Introgressing the tolerance into modern tomato hybrid lines, results in up to 20% yield increase, showing that limitations for crop productivity, caused by the adaptation of plants to the terrestrial 24-h day/night cycle, can be overcome.

  4. Flowering Locus C’s Lessons: Conserved Chromatin Switches Underpinning Developmental Timing and Adaptation1

    PubMed Central

    Hepworth, Jo; Dean, Caroline

    2015-01-01

    Analysis of how seasonal cues influence the timing of the floral transition has revealed many important principles for how epigenetic regulation can integrate a variety of environmental cues with developmental signals. The study of the pathways that necessitate overwintering in plants and their ability to respond to prolonged cold (the vernalization requirement and response pathways) has elaborated different chromatin regulatory pathways and the involvement of noncoding RNAs. The major target of these vernalization pathways in Arabidopsis (Arabidopsis thaliana) is Flowering Locus C (FLC). A relatively simple picture of FLC regulation is emerging of a few core complexes and mechanisms that antagonize each other’s actions. This balance provides a fine degree of control that has nevertheless permitted evolution of a wide range of natural variation in vernalization in Arabidopsis. Similar simple routes of adaptation may underlie life history variation between species. PMID:26149571

  5. The agr Locus Regulates Virulence and Colonization Genes in Clostridium difficile 027

    PubMed Central

    Martin, Melissa J.; Clare, Simon; Goulding, David; Faulds-Pain, Alexandra; Barquist, Lars; Browne, Hilary P.; Pettit, Laura; Dougan, Gordon; Lawley, Trevor D.

    2013-01-01

    The transcriptional regulator AgrA, a member of the LytTR family of proteins, plays a key role in controlling gene expression in some Gram-positive pathogens, including Staphylococcus aureus and Enterococcus faecalis. AgrA is encoded by the agrACDB global regulatory locus, and orthologues are found within the genome of most Clostridium difficile isolates, including the epidemic lineage 027/BI/NAP1. Comparative RNA sequencing of the wild type and otherwise isogenic agrA null mutant derivatives of C. difficile R20291 revealed a network of approximately 75 differentially regulated transcripts at late exponential growth phase, including many genes associated with flagellar assembly and function, such as the major structural subunit, FliC. Other differentially regulated genes include several involved in bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) synthesis and toxin A expression. C. difficile 027 R20291 agrA mutant derivatives were poorly flagellated and exhibited reduced levels of colonization and relapses in the murine infection model. Thus, the agr locus likely plays a contributory role in the fitness and virulence potential of C. difficile strains in the 027/BI/NAP1 lineage. PMID:23772065

  6. Role of the sar locus of Staphylococcus aureus in induction of endocarditis in rabbits.

    PubMed Central

    Cheung, A L; Yeaman, M R; Sullam, P M; Witt, M D; Bayer, A S

    1994-01-01

    A regulatory locus on the Staphylococcus aureus chromosome, designated sar, is involved in the expression of cell wall proteins, some of which are potentially important in the pathogenesis of endocarditis. For instance, mutant 11D2 (sar::Tn917LTV1) was found to bind substantially less to matrix proteins (i.e., fibrinogen and fibronectin) than parent strain DB. Remarkably, these two strains did not differ in other phenotypes considered important in the initiation of endocarditis (e.g., binding to platelets and resistance to platelet-derived microbicidal proteins). The isogenic pair were compared for pathogenicity in a rabbit endocarditis model. There were significant differences in infectivity rates between the two strains (71 and 88% for DB versus 17 and 42% for mutant 11D2 at inocula of 10(3) and 10(4) CFU, respectively). In early adherence studies, parent DB adhered substantially better than the mutant to valvular vegetations at an inoculum of 10(6) CFU (P = 0.05). Southern blot analysis of colonies indicated that the location of the Tn917LTV1 insert in mutant 11D2 remained stable after animal passage. In vitro adherence assays revealed that mutant 11D2 was less adherent to cultured human endothelium than parent DB. These studies suggest that the sar locus is involved in the initial adherence of S. aureus to the fibrin-platelet-endothelium matrix on damaged valvular endothelium. Images PMID:8168933

  7. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus

    PubMed Central

    Musunuru, Kiran; Strong, Alanna; Frank-Kamenetsky, Maria; Lee, Noemi E.; Ahfeldt, Tim; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James J.; Muchmore, Brian; Prokunina-Olsson, Ludmila; Hall, Jennifer L.; Schadt, Eric E.; Morales, Carlos R.; Lund-Katz, Sissel; Phillips, Michael C.; Wong, Jamie; Cantley, William; Racie, Timothy; Ejebe, Kenechi G.; Orho-Melander, Marju; Melander, Olle; Koteliansky, Victor; Fitzgerald, Kevin; Krauss, Ronald M.; Cowan, Chad A.; Kathiresan, Sekar; Rader, Daniel J.

    2011-01-01

    Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 as strongly associated with both serum low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP transcription factor binding site and alters the hepatic expression of the SORT1 gene. With siRNA knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes. PMID:20686566

  8. The agr locus regulates virulence and colonization genes in Clostridium difficile 027.

    PubMed

    Martin, Melissa J; Clare, Simon; Goulding, David; Faulds-Pain, Alexandra; Barquist, Lars; Browne, Hilary P; Pettit, Laura; Dougan, Gordon; Lawley, Trevor D; Wren, Brendan W

    2013-08-01

    The transcriptional regulator AgrA, a member of the LytTR family of proteins, plays a key role in controlling gene expression in some Gram-positive pathogens, including Staphylococcus aureus and Enterococcus faecalis. AgrA is encoded by the agrACDB global regulatory locus, and orthologues are found within the genome of most Clostridium difficile isolates, including the epidemic lineage 027/BI/NAP1. Comparative RNA sequencing of the wild type and otherwise isogenic agrA null mutant derivatives of C. difficile R20291 revealed a network of approximately 75 differentially regulated transcripts at late exponential growth phase, including many genes associated with flagellar assembly and function, such as the major structural subunit, FliC. Other differentially regulated genes include several involved in bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) synthesis and toxin A expression. C. difficile 027 R20291 agrA mutant derivatives were poorly flagellated and exhibited reduced levels of colonization and relapses in the murine infection model. Thus, the agr locus likely plays a contributory role in the fitness and virulence potential of C. difficile strains in the 027/BI/NAP1 lineage.

  9. A genetic locus essential for formate-dependent growth of Bradyrhizobium japonicum.

    PubMed Central

    McClung, C R; Chelm, B K

    1987-01-01

    A genetic locus essential for the formate-dependent growth of Bradyrhizobium japonicum was isolated by complementation of ethyl methanesulfonate-induced mutants with a cosmid gene library of B. japonicum DNA. Three related cosmids containing 18.7 kilobase pairs of B. japonicum DNA in common were identified as being able to restore formate-dependent growth capability to mutants lacking either ribulosebisphosphate carboxylase or both ribulosebisphosphate carboxylase and phosphoribulokinase activities. To further localize the complementing gene(s), a series of four deletions spanning a total of 16.1 kilobase pairs were introduced into the B. japonicum chromosome. Each resulting deletion mutant lacked formate dehydrogenase activity and lacked ribulosebisphosphate carboxylase activity and immunologically detectable protein. Three of the four also lacked phosphoribulokinase activity. Two other mutants in which the deletion-bearing recombinant plasmid had integrated into the chromosome also lacked ribulosebisphosphate carboxylase activity and protein and phosphoribulokinase activities. The genetic locus defined by these mutants could contain the structural genes for these enzymes or a regulatory gene(s) controlling their expression or both. Images PMID:3036781

  10. β-Globin locus control region HS2 and HS3 interact structurally and functionally

    PubMed Central

    Jackson, David A.; McDowell, Jennifer C.; Dean, Ann

    2003-01-01

    The overall structure of the DNase I hypersensitive sites (HSs) that comprise the β-globin locus control region (LCR) is highly conserved among mammals, implying that the HSs have conserved functions. However, it is not well understood how the LCR HSs, either individually or collectively, activate transcription. We analyzed the interactions of HS2, HS3 and HS4 with the human ε- and β-globin genes in chromatinized episomes in fetal/embryonic K562 cells. Only HS2 activates transcription of the ε-globin gene, while all three HSs activate the β-globin gene. HS3 stimulates the β-globin gene constitutively, but HS2 and HS4 transactivation requires expression of the transcription factor EKLF, which is not present in K562 cells but is required for β-globin expression in vivo. To begin addressing how the individual HSs may interact with one another in a complex, we linked the β-globin gene to both the HS2 and HS3. HS2 and HS3 together resulted in synergistic stimulation of β-globin transcription. Unexpectedly, mutated, inactive forms of HS2 impeded the activation of the β-globin gene by HS3. Thus, there appear to be distinct interactions among the HSs and between the HSs and the globin genes. These preferential, non-exclusive interactions may underlie an important structural and functional cooperativity among the regulatory sequences of the β-globin locus in vivo. PMID:12582237

  11. On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions

    NASA Astrophysics Data System (ADS)

    Tarpine, Ryan; Istrail, Sorin

    The regulatory genome is about the “system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution” (E.H. Davidson. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, 2006). Information processing in the regulatory genome is done through regulatory states, defined as sets of transcription factors (sequence-specific DNA binding proteins which determine gene expression) that are expressed and active at the same time. The core information processing machinery consists of modular DNA sequence elements, called cis-modules, that interact with transcription factors. The cis-modules “read” the information contained in the regulatory state of the cell through transcription factor binding, “process” it, and directly or indirectly communicate with the basal transcription apparatus to determine gene expression. This endowment of each gene with the information-receiving capacity through their cis-regulatory modules is essential for the response to every possible regulatory state to which it might be exposed during all phases of the life cycle and in all cell types. We present here a set of challenges addressed by our CYRENE research project aimed at studying the cis-regulatory code of the regulatory genome. The CYRENE Project is devoted to (1) the construction of a database, the cis-Lexicon, containing comprehensive information across species about experimentally validated cis-regulatory modules; and (2) the software development of a next-generation genome browser, the cis-Browser, specialized for the regulatory genome. The presentation is anchored on three main computational challenges: the Gene Naming Problem, the Consensus Sequence Bottleneck Problem, and the Logic Function Inference Problem.

  12. Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding.

    PubMed

    Andrey, Guillaume; Schöpflin, Robert; Jerković, Ivana; Heinrich, Verena; Ibrahim, Daniel M; Paliou, Christina; Hochradel, Myriam; Timmermann, Bernd; Haas, Stefan; Vingron, Martin; Mundlos, Stefan

    2017-02-01

    Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location, and dynamics of their associated regulatory elements are unknown. In this work, we characterized the three-dimensional chromatin microarchitecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq, and RNA-seq in forelimb, hindlimb at three developmental stages, and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains. By combining chromatin marks and interaction peaks, we annotated more than 1000 putative limb enhancers and their associated genes. Moreover, the analysis of chromatin interactions revealed two regimes of chromatin folding, one producing interactions stable across tissues and stages and another one associated with tissue and/or stage-specific interactions. Whereas stable interactions associate strongly with CTCF/RAD21 binding, the intensity of variable interactions correlates with changes in underlying chromatin modifications, specifically at the viewpoint and at the interaction site. In conclusion, this comprehensive data set provides a resource for the characterization of hundreds of limb-associated regulatory landscapes and a framework to interpret the chromatin folding dynamics observed during embryogenesis.

  13. Alkylrhodamines enhance the toxicity of clotrimazole and benzalkonium chloride by interfering with yeast pleiotropic ABC-transporters.

    PubMed

    Knorre, Dmitry A; Besedina, Elizaveta; Karavaeva, Iuliia E; Smirnova, Ekaterina A; Markova, Olga V; Severin, Fedor F

    2016-06-01

    ABC-transporters with broad substrate specificity are responsible for pathogenic yeast resistance to antifungal compounds. Here we asked whether highly hydrophobic chemicals with delocalized positive charge can be used to overcome the resistance. Such molecules efficiently penetrate the plasma membrane and accumulate inside the cells. We reasoned that these properties can convert an active efflux of the compounds into a futile cycle thus interfering with the extrusion of the antibiotics. To test this, we studied the effects of several alkylated rhodamines on the drug resistance of yeast Saccharomyces cerevisiae We found that octylrhodamine synergetically increases toxicity of Pdr5p substrate-clotrimazole, while the others were less effective. Next, we compared the contributions of three major pleiotropic ABC-transporters (Pdr5p, Yor1p, Snq2p) on the accumulation of the alkylated rhodamines. While all of the tested compounds were extruded by Pdr5p, Yor1p and Snq2p showed narrower substrate specificity. Interestingly, among the tested alkylated rhodamines, inactivation of Pdr5p had the strongest effect on the accumulation of octylrhodamine inside the cells, which is consistent with the fact that clotrimazole is a substrate of Pdr5p. As alkylated rhodamines were shown to be non-toxic on mice, our study makes them potential components of pharmacological antifungal compositions.

  14. The structure of the pleiotropic transcription regulator CodY provides insight into its GTP-sensing mechanism

    PubMed Central

    Han, Ah-reum; Kang, Hye-Ri; Son, Jonghyeon; Kwon, Do Hoon; Kim, Sulhee; Lee, Woo Cheol; Song, Hyun Kyu; Song, Moon Jung; Hwang, Kwang Yeon

    2016-01-01

    GTP and branched-chain amino acids (BCAAs) are metabolic sensors that are indispensable for the determination of the metabolic status of cells. However, their molecular sensing mechanism remains unclear. CodY is a unique global transcription regulator that recognizes GTP and BCAAs as specific signals and affects expression of more than 100 genes associated with metabolism. Herein, we report the first crystal structures of the full-length CodY complex with sensing molecules and describe their functional states. We observed two different oligomeric states of CodY: a dimeric complex of CodY from Staphylococcus aureus with the two metabolites GTP and isoleucine, and a tetrameric form (apo) of CodY from Bacillus cereus. Notably, the tetrameric state shows in an auto-inhibitory manner by blocking the GTP-binding site, whereas the binding sites of GTP and isoleucine are clearly visible in the dimeric state. The GTP is located at a hinge site between the long helical region and the metabolite-binding site. Together, data from structural and electrophoretic mobility shift assay analyses improve understanding of how CodY senses GTP and operates as a DNA-binding protein and a pleiotropic transcription regulator. PMID:27596595

  15. RahU: An inducible and functionally pleiotropic protein in Pseudomonas aeruginosa modulates innate immunity and inflammation in host cells

    PubMed Central

    Rao, Jayasimha; Elliott, Michael R.; Leitinger, Norbert; Jensen, Roderick V.; Goldberg, Joanna B.; Amin, Ashok R.

    2012-01-01

    The aim of this study was to define the functional role of a recently identified RahU protein from Pseudomonas aeruginosa in macrophages and its role in bacterial defense. Recombinant (r)-RahU had no significant effect on cell apoptosis or cell viability in human monocytic THP-1 cells. Gene expression array of murine macrophage cells (RAW 264.7) stimulated with LPS showed modulation of common transcripts involved in inflammation. Functional cellular analysis showed RAW cells incubated with r-RahU at 1.0–10 µg/ml (0.06–0.6 µM) inhibited accumulation of nitric oxide (NO) in the presence of LPS by 10 to 50%. The IC50 of r-RahU (0.6 µM) was distinct from the known inhibitors of NO production: prednisone (50 µM) and L-NMMA (100 µM). rRahU also significantly inhibited chemotactic activity of THP-1 cells toward CCL2 or chemotactic supernatants from apoptotic T-cells. These reports show previously unknown pleiotropic properties of RahU in modulating both microbial physiology and host innate immunity. PMID:21704311

  16. An increase in melatonin in transgenic rice causes pleiotropic phenotypes, including enhanced seedling growth, delayed flowering, and low grain yield.

    PubMed

    Byeon, Yeong; Back, Kyoungwhan

    2014-05-01

    No previous reports have described the effects of an increase in endogenous melatonin levels on plant yield and reproduction. Here, the phenotypes of melatonin-rich transgenic rice plants overexpressing sheep serotonin N-acetyltransferase were investigated under field conditions. Early seedling growth of melatonin-rich transgenic rice was greatly accelerated, with enhanced biomass relative to the wild type (WT). However, flowering was delayed by 1 wk in the transgenic lines compared with the WT. Grain yields of the melatonin-rich transgenic lines were reduced by 33% on average. Other phenotypes also varied among the transgenic lines. For example, the transgenic line S1 exhibited greater height and biomass than the WT, while the S10 transgenic line showed diminished height and an increase in panicle numbers per plant. The expression levels of Oryza sativa homeobox1 (OSH1) and TEOSINTE BRANCHED1 (TB1) genes, two key regulators of meristem initiation and maintenance, were not altered in the transgenic lines. These data demonstrate that an alteration of endogenous melatonin levels leads to pleiotropic effects such as height, biomass, panicle number, flowering time, and grain yield, indicating that melatonin behaves as a signaling molecule in plant growth and reproduction.

  17. A new pleiotropic mutation causing defective carbohydrate uptake in Escherichia coli K-12: isolation, mapping, and preliminary characterization.

    PubMed Central

    Mahajan, S K; Vartak, N B; Datta, A R

    1988-01-01

    A new pleiotropic mutation, designated cup-1 (for carbohydrate uptake), which impairs the ability of Escherichia coli cells to grow on a large number of phosphotransferase system (PTS) and non-PTS carbohydrates by blocking their entry into the cells, has been isolated, partially characterized, and mapped. The mutants grew poorly even on rich and glucose minimal media. Fast-growing revertants rapidly accumulated in cultures grown on either of the above two media and made stable maintenance of the mutation difficult. Several extragenic suppressor mutations that permitted cup cells to grow on specific single sugars or groups of sugars have been isolated. One such suppressor, which enabled cup cells to grow as well on glycerol minimal medium as their wild-type parent, has been helpful in stably maintaining these cells in this medium. cup-1 has been mapped to 97 min on the standard E. coli map. It cotransduced with a transposon Tn10 inserted clockwise to it and (very weakly) with uxuA. Surprisingly, it failed to cotransduce with pyrB, argI, or valS, three markers located nearby but counterclockwise to it. In F' merodiploids, cup-1 was dominant over its cup+ allele. Cyclic AMP permitted growth of cup-1 cells on some sugars but not all. Apparently, reduced cyclic AMP level and therefore noninduction of several sugar operons is one but not the only effect of cup. PMID:2836361

  18. Pleiotropic quantitative trait loci contribute to population divergence in traits associated with life-history variation in Mimulus guttatus.

    PubMed

    Hall, Megan C; Basten, Christopher J; Willis, John H

    2006-03-01

    Evolutionary biologists seek to understand the genetic basis for multivariate phenotypic divergence. We constructed an F2 mapping population (N = 539) between two distinct populations of Mimulus guttatus. We measured 20 floral, vegetative, and life-history characters on parents and F1 and F2 hybrids in a common garden experiment. We employed multitrait composite interval mapping to determine the number, effect, and degree of pleiotropy in quantitative trait loci (QTL) affecting divergence in floral, vegetative, and life-history characters. We detected 16 QTL affecting floral traits; 7 affecting vegetative traits; and 5 affecting selected floral, vegetative, and life-history traits. Floral and vegetative traits are clearly polygenic. We detected a few major QTL, with all remaining QTL of small effect. Most detected QTL are pleiotropic, implying that the evolutionary shift between these annual and perennial populations is constrained. We also compared the genetic architecture controlling floral trait divergence both within (our intraspecific study) and between species, on the basis of a previously published analysis of M. guttatus and M. nasutus. Eleven of our 16 floral QTL map to approximately the same location in the interspecific map based on shared, collinear markers, implying that there may be a shared genetic basis for floral divergence within and among species of Mimulus.

  19. Pleiotropic Quantitative Trait Loci Contribute to Population Divergence in Traits Associated With Life-History Variation in Mimulus guttatus

    PubMed Central

    Hall, Megan C.; Basten, Christopher J.; Willis, John H.

    2006-01-01

    Evolutionary biologists seek to understand the genetic basis for multivariate phenotypic divergence. We constructed an F2 mapping population (N = 539) between two distinct populations of Mimulus guttatus. We measured 20 floral, vegetative, and life-history characters on parents and F1 and F2 hybrids in a common garden experiment. We employed multitrait composite interval mapping to determine the number, effect, and degree of pleiotropy in quantitative trait loci (QTL) affecting divergence in floral, vegetative, and life-history characters. We detected 16 QTL affecting floral traits; 7 affecting vegetative traits; and 5 affecting selected floral, vegetative, and life-history traits. Floral and vegetative traits are clearly polygenic. We detected a few major QTL, with all remaining QTL of small effect. Most detected QTL are pleiotropic, implying that the evolutionary shift between these annual and perennial populations is constrained. We also compared the genetic architecture controlling floral trait divergence both within (our intraspecific study) and between species, on the basis of a previously published analysis of M. guttatus and M. nasutus. Eleven of our 16 floral QTL map to approximately the same location in the interspecific map based on shared, collinear markers, implying that there may be a shared genetic basis for floral divergence within and among species of Mimulus. PMID:16361232

  20. Site-Directed Mutagenesis of the Nidovirus Replicative Endoribonuclease NendoU Exerts Pleiotropic Effects on the Arterivirus Life Cycle

    PubMed Central

    Posthuma, Clara C.; Nedialkova, Danny D.; Zevenhoven-Dobbe, Jessika C.; Blokhuis, Jeroen H.; Gorbalenya, Alexander E.; Snijder, Eric J.

    2006-01-01

    The highly conserved NendoU replicative domain of nidoviruses (arteriviruses, coronaviruses, and roniviruses) belongs to a small protein family whose cellular branch is prototyped by XendoU, a Xenopus laevis endoribonuclease involved in nucleolar RNA processing. Recently, sequence-specific in vitro endoribonuclease activity was demonstrated for the NendoU-containing nonstructural protein (nsp) 15 of several coronaviruses. To investigate the biological role of this novel enzymatic activity, we have characterized a comprehensive set of arterivirus NendoU mutants. Deleting parts of the NendoU domain from nsp11 of equine arteritis virus was lethal. Site-directed mutagenesis of conserved residues exerted pleiotropic effects. In a first-cycle analysis, replacement of two conserved Asp residues in the C-terminal part of NendoU rendered viral RNA synthesis and virus production undetectable. In contrast, mutagenesis of other conserved residues, including two putative catalytic His residues that are absolutely conserved in NendoU and cellular homologs, produced viable mutants displaying reduced plaque sizes (20 to 80% reduction) and reduced yields of infectious progeny of up to 5 log units. A more detailed analysis of these mutants revealed a moderate reduction in RNA synthesis, with subgenomic RNA synthesis consistently being more strongly affected than genome replication. Our data suggest that the arterivirus nsp11 is a multifunctional protein with a key role in viral RNA synthesis and additional functions in the viral life cycle that are as yet poorly defined. PMID:16439522

  1. Insertional Inactivation of Genes Encoding the Crystalline Inclusion Proteins of Photorhabdus luminescens Results in Mutants with Pleiotropic Phenotypes

    PubMed Central

    Bintrim, Scott B.; Ensign, Jerald C.

    1998-01-01

    The entomopathogenic bacterium Photorhabdus luminescens exhibits phase variation when cultured in vitro. The variant forms of P. luminescens are pleiotropic and are designated phase I and phase II variants. One of the characteristic phenotypes of phase I cells is the production of two types of intracellular protein inclusions. The genes encoding the protein monomers that form these inclusions, designated cipA and cipB, were cloned and characterized. cipA and cipB encode hydrophobic proteins of 11,648 and 11,308 Da, respectively. The deduced amino acid sequences of CipA and CipB have no significant amino acid sequence similarity to any other known protein but have 25% identity and 49% similarity to each other. Insertional inactivation of cipA or cipB in phase I cells of P. luminescens produced mutants that differ from phase I cells in bioluminescence, the pattern and activities of extracellular products, biochemical traits, adsorption of dyes, and ability to support nematode growth and reproduction. In general, the cip mutants were phenotypically more similar to each other than to either phase I or phase II variants. PMID:9495767

  2. Gas1 is a pleiotropic regulator of cellular functions: from embryonic development to molecular actions in cancer gene therapy.

    PubMed

    Segovia, José; Zarco, Natanael

    2014-01-01

    Cellular homeostasis is governed by a precise regulation of the molecular mechanisms of action of several proteins in a given time. There is a group of proteins that have a particular role depending on the cellular context in which they are present and are known as pleiotropic proteins. The Gas1 (Growth Arrest Specific 1) gene was isolated from a subtraction library from serum arrested versus growing NIH3T3 mouse fibroblast. Gas1 is a member of the alpha receptors (GFRα) for the family of GDNF ligands (GFL), we have previously shown that Gas1 acts as a negative modulator of the GDNF-induced intracellular signaling and induces cell arrest and apoptosis. This modulating activity is the cause of the capacity of Gas1 to act as a tumor suppressor. On the other hand, several studies have shown the interaction between Gas1 and Hh (Hedgehog) proteins to potentiate the positive regulation of this pathway, which is involved in the development of the nervous system, and in both the origin and progression of different tumors. This review summarizes our current understanding of the structure of Gas1 and the molecular mechanism of action in different cellular functions, both during embryonic development, in the adult and its effects inhibiting cell growth and inducing apoptosis of cancer cells.

  3. Role of ribosomal protein S12 in peptide chain elongation: analysis of pleiotropic, streptomycin-resistant mutants of Escherichia coli.

    PubMed Central

    Zengel, J M; Young, R; Dennis, P P; Nomura, M

    1977-01-01

    Some of the spontaneous streptomycin-resistant mutants of Escherichia coli strain C600 exhibit pleiotropic effects in addition to the antibiotic resistance. These effects include decreased growth rates, reduced levels of certain enzymes, and poor support of bacteriophage growth. One of these mutants, strain SM3, was studied further. We have examined the question of whether the reduced growth rate of the mutant SM3 is related to the reduction in relative amounts of ribosomes or to the reduction in the efficiency of ribosomes in protein synthesis. Measurements of alpha, the differential synthesis rate of ribosomal protein, revealed that the protein synthesis effeciency of ribosomes from the mutant strain SM3 was reduced about twofold relative to that of the parent strain C600. Measurements of the induction lag for beta-galactosidase and of the synthesis time of several different molecular-weight classes of proteins indicated that the mutation resulted in a marked reduction in the peptide chain growth rate. This reduction in the chain growth rate probably accounted for most of the observed reduction in the growth rate of the mutant strain. These experimental results show that the strA gene product, the S12 protein of the 30S subunit, is involved in some aspect of protein chain elongation. Presumably this involvement occurs during the messenger ribonucleic acid-directed binding of transfer ribonucleic acid to the ribosome. PMID:321423

  4. Role of ribosomal protein S12 in peptide chain elongation: analysis of pleiotropic, streptomycin-resistant mutants of Escherichia coli.

    PubMed

    Zengel, J M; Young, R; Dennis, P P; Nomura, M

    1977-03-01

    Some of the spontaneous streptomycin-resistant mutants of Escherichia coli strain C600 exhibit pleiotropic effects in addition to the antibiotic resistance. These effects include decreased growth rates, reduced levels of certain enzymes, and poor support of bacteriophage growth. One of these mutants, strain SM3, was studied further. We have examined the question of whether the reduced growth rate of the mutant SM3 is related to the reduction in relative amounts of ribosomes or to the reduction in the efficiency of ribosomes in protein synthesis. Measurements of alpha, the differential synthesis rate of ribosomal protein, revealed that the protein synthesis effeciency of ribosomes from the mutant strain SM3 was reduced about twofold relative to that of the parent strain C600. Measurements of the induction lag for beta-galactosidase and of the synthesis time of several different molecular-weight classes of proteins indicated that the mutation resulted in a marked reduction in the peptide chain growth rate. This reduction in the chain growth rate probably accounted for most of the observed reduction in the growth rate of the mutant strain. These experimental results show that the strA gene product, the S12 protein of the 30S subunit, is involved in some aspect of protein chain elongation. Presumably this involvement occurs during the messenger ribonucleic acid-directed binding of transfer ribonucleic acid to the ribosome.

  5. Meta-analysis of quantitative pleiotropic traits for next-generation sequencing with multivariate functional linear models.

    PubMed

    Chiu, Chi-Yang; Jung, Jeesun; Chen, Wei; Weeks, Daniel E; Ren, Haobo; Boehnke, Michael; Amos, Christopher I; Liu, Aiyi; Mills, James L; Ting Lee, Mei-Ling; Xiong, Momiao; Fan, Ruzong

    2017-02-01

    To analyze next-generation sequencing data, multivariate functional linear models are developed for a meta-analysis of multiple studies to connect genetic variant data to multiple quantitative traits adjusting for covariates. The goal is to take the advantage of both meta-analysis and pleiotropic analysis in order to improve power and to carry out a unified association analysis of multiple studies and multiple traits of complex disorders. Three types of approximate F -distributions based on Pillai-Bartlett trace, Hotelling-Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants. Simulation analysis is performed to evaluate false-positive rates and power of the proposed tests. The proposed methods are applied to analyze lipid traits in eight European cohorts. It is shown that it is more advantageous to perform multivariate analysis than univariate analysis in general, and it is more advantageous to perform meta-analysis of multiple studies instead of analyzing the individual studies separately. The proposed models require individual observations. The value of the current paper can be seen at least for two reasons: (a) the proposed methods can be applied to studies that have individual genotype data; (b) the proposed methods can be used as a criterion for future work that uses summary statistics to build test statistics to meta-analyze the data.

  6. Locus of control and cerebral asymmetry.

    PubMed

    De Brabander, B; Boone, C; Gerits, P

    1992-08-01

    Data about the lack of synchronism of flexor carpi ulnaris peak EMG values of bimanual reactions during a semantic and during a visuospatial discrimination reaction time task are reported. The effects of type of task as well as the presence or absence of an unexpected stimulus preceding the reaction stimulus on lack of synchronism clearly depend upon the locus of control of the subjects, as measured on Rotter's I-E scale. On the basis of several arguments it is proposed that the measure of lack of synchronism reflects in an opposite sense the amount of dopaminergic activation or motor readiness in the sense in which Pribram and McGuinness in 1975 and Tucker and Williamson in 1984 have defined these concepts. The results for 15 women and 18 men show that more internally oriented subjects are more activated by a semantic task and by an unexpected preparatory stimulus in this type of task than more externally oriented subjects. The opposite appears to hold on the visuospatial task and unexpected preparatory stimuli therein. Together with earlier findings about reaction times and a number of relevant findings in the literature, the results are interpreted as indicative of basic differences in asymmetric tonic activation of the cerebral hemispheres between more internally and more externally oriented subjects. A model is proposed to explain phasic activating effects which ensue when tonically more left- or right-activated subjects perform left- or right-hemisphere tasks and when supplementary irrelevant stimuli are received.

  7. Autism, fever, epigenetics and the locus coeruleus.

    PubMed

    Mehler, Mark F; Purpura, Dominick P

    2009-03-01

    Some children with autism spectrum disorders (ASD) exhibit improved behaviors and enhanced communication during febrile episodes. We hypothesize that febrigenesis and the behavioral-state changes associated with fever in autism depend upon selective normalization of key components of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system. We posit that autistic behaviors result from developmental dysregulation of LC-NA system specification and neural network deployment and modulation linked to the core behavioral features of autism. Fever transiently restores the modulatory functions of the LC-NA system and ameliorates autistic behaviors. Fever-induced reversibility of autism suggests preserved functional integrity of widespread neural networks subserving the LC-NA system and specifically the subsystems involved in mediating the cognitive and behavioral repertoires compromised in ASD. Alterations of complex gene-environmental interactions and associated epigenetic mechanisms during seminal developmental critical periods are viewed as instrumental in LC-NA dysregulation as emphasized by the timing and severity of prenatal maternal stressors on autism prevalence. Our hypothesis has implications for a rational approach to further interrogate the interdisciplinary etiology of ASD and for designing novel biological detection systems and therapeutic agents that target the LC-NA system's diverse network of pre- and postsynaptic receptors, intracellular signaling pathways and dynamic epigenetic remodeling processes involved in their regulation and functional plasticity.

  8. THE LOCUS COERULEUS AND CENTRAL CHEMOSENSITIVITY

    PubMed Central

    Gargaglioni, Luciane H.; Hartzler, Lynn K.; Putnam, Robert W.

    2010-01-01

    The locus coeruleus (LC) lies in the dorsal pons and supplies noradrenergic (NA) input to many regions of the brain, including respiratory control areas. The LC may provide tonic input for basal respiratory drive and is involved in central chemosensitivity since focal acidosis of the region stimulates ventilation and ablation reduces CO2-induced increased ventilation. The output of LC is modulated by both serotonergic and glutamatergic inputs. A large percentage of LC neurons are intrinsically activated by hypercapnia. This percentage and the magnitude of their response are highest in young neonates and decrease dramatically after postnatal day P10. The cellular bases for intrinsic chemosensitivity of LC neurons are comprised of multiple factors, primary among them being reduced extracellular and intracellular pH, which inhibit inwardly rectifying and voltage-gated K+ channels, and activate L-type Ca2+ channels. Activation of KCa channels in LC neurons may limit their ultimate response to hypercapnia. Finally, the LC mediates central chemosensitivity and contains pH-sensitive neurons in amphibians, suggesting that the LC has a long-standing phylogenetic role in respiratory control. PMID:20435170

  9. Sequence variation within the fragile X locus.

    PubMed

    Mathews, D J; Kashuk, C; Brightwell, G; Eichler, E E; Chakravarti, A

    2001-08-01

    The human genome provides a reference sequence, which is a template for resequencing studies that aim to discover and interpret the record of common ancestry that exists in extant genomes. To understand the nature and pattern of variation and linkage disequilibrium comprising this history, we present a study of approximately 31 kb spanning an approximately 70 kb region of FMR1, sequenced in a sample of 20 humans (worldwide sample) and four great apes (chimp, bonobo, and gorilla). Twenty-five polymorphic sites and two insertion/deletions, distributed in 11 unique haplotypes, were identified among humans. Africans are the only geographic group that do not share any haplotypes with other groups. Parsimony analysis reveals two main clades and suggests that the four major human geographic groups are distributed throughout the phylogenetic tree and within each major clade. An African sample appears to be most closely related to the common ancestor shared with the three other geographic groups. Nucleotide diversity, pi, for this sample is 2.63 +/- 6.28 x 10(-4). The mutation rate, mu is 6.48 x 10(-10) per base pair per year, giving an ancestral population size of approximately 6200 and a time to the most recent common ancestor of approximately 320,000 +/- 72,000 per base pair per year. Linkage disequilibrium (LD) at the FMR1 locus, evaluated by conventional LD analysis and by the length of segment shared between any two chromosomes, is extensive across the region.

  10. Rationales for regulatory activity

    SciTech Connect

    Perhac, R.M.

    1997-02-01

    The author provides an outline which touches on the types of concerns about risk evaluation which are addressed in the process of establishing regulatory guides. Broadly he says regulatory activity serves three broad constituents: (1) Paternalism (private risk); (2) Promotion of social welfare (public risks); (3) Protection of individual rights (public risks). He then discusses some of the major issues encountered in reaching a decision on what is an acceptable level of risk within each of these areas, and how one establishes such a level.

  11. Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.

    PubMed

    Camp, Nicola J; Lin, Wei-Yu; Bigelow, Alex; Burghel, George J; Mosbruger, Timothy L; Parry, Marina A; Waller, Rosalie G; Rigas, Sushilaben H; Tai, Pei-Yi; Berrett, Kristofer; Rajamanickam, Venkatesh; Cosby, Rachel; Brock, Ian W; Jones, Brandt; Connley, Dan; Sargent, Robert; Wang, Guoying; Factor, Rachel E; Bernard, Philip S; Cannon-Albright, Lisa; Knight, Stacey; Abo, Ryan; Werner, Theresa L; Reed, Malcolm W R; Gertz, Jason; Cox, Angela

    2016-04-01

    The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Myopia as a latent phenotype of a pleiotropic gene positively selected for facilitating neurocognitive development, and the effects of environmental factors in its expression.

    PubMed

    Mak, W; Kwan, M W M; Cheng, T S; Chan, K H; Cheung, R T F; Ho, S L

    2006-01-01

    Myopia has become an almost pandemic problem in many populations. There are compelling evidence to suggest that myopia is a hereditary condition. However, myopia would constitute a definite selection disadvantage during most stages of human evolution, which is incompatible with its moderate to high prevalence in most modern populations. The rapid upsurge of myopia over just a few decades also implies that its inheritance does not follow any of the usual patterns, and environmental factors may have an important role in precipitating its occurrence in those who are genetically predisposed. Previous studies showed that myopes were, on average, more intelligent than non-myopes, and this association had been attributed to a biological link between eye growth and brain development. We propose a pleiotropic genetic model to explain the atypical epidemiologic and inheritance pattern of myopia and its relationship with neurocognitive development. This pleiotropic gene was positively selected for its facilitation of human intelligence. The myopic component is a latent phenotype; myopia will not be expressed unless some novel external factors are encountered (i.e. a "quirk" phenomenon). Therefore, the myopic component was selectively neutral in our ancestral environment. The net gain in Darwinian fitness enables the pleiotropic gene to attain a high frequency in the human population, as reflected by our current prevalence of myopia.

  13. Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus.

    PubMed

    Rojo, Rocio; Pridans, Clare; Langlais, David; Hume, David A

    2017-08-15

    The proliferation, differentiation, and survival of cells of the macrophage lineage depends upon signals from the macrophage colony-stimulating factor (CSF) receptor (CSF1R). CSF1R is expressed by embryonic macrophages and induced early in adult hematopoiesis, upon commitment of multipotent progenitors to the myeloid lineage. Transcriptional activation of CSF1R requires interaction between members of the E26 transformation-specific family of transcription factors (Ets) (notably PU.1), C/EBP, RUNX, AP-1/ATF, interferon regulatory factor (IRF), STAT, KLF, REL, FUS/TLS (fused in sarcoma/ranslocated in liposarcoma) families, and conserved regulatory elements within the mouse and human CSF1R locus. One element, the Fms-intronic regulatory element (FIRE), within intron 2, is conserved functionally across all the amniotes. Lineage commitment in multipotent progenitors also requires down-regulation of specific transcription factors such as MYB, FLI1, basic leucine zipper transcriptional factor ATF-like (BATF3), GATA-1, and PAX5 that contribute to differentiation of alternative lineages and repress CSF1R transcription. Many of these transcription factors regulate each other, interact at the protein level, and are themselves downstream targets of CSF1R signaling. Control of CSF1R transcription involves feed-forward and feedback signaling in which CSF1R is both a target and a participant; and dysregulation of CSF1R expression and/or function is associated with numerous pathological conditions. In this review, we describe the regulatory network behind CSF1R expression during differentiation and development of cells of the mononuclear phagocyte system. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  14. The internet and locus of control in older adults.

    PubMed Central

    Campbell, Robert J.; Harris, Kimberly D.; Wabby, James

    2002-01-01

    OBJECTIVE: To investigate how training older adults to find medical information using the Internet affects their locus of control. METHODS: Quantitative methods were utilized. Specifically, the Multidimensional Health Locus of Control survey was distributed at the onset of each seminar and again at the conclusion. RESULTS: Paired t-tests revealed that the subjects did not change their locus of control regarding their health beliefs over the period of the seminar. However, there was statistical significance with regard to eight specific questions. CONCLUSION: Subjects scored high on their level of internal locus of control coming into the study. The majority of subjects had already learned to use the computer, owned a home computer, and had access to the Internet, but had not used the Internet to search for healthcare information. The challenge continues to be reaching those older adults who have not encountered the computer and the Internet. PMID:12463794

  15. Multidimensional profiles of health locus of control in Hispanic Americans

    PubMed Central

    Champagne, Brian R; Fox, Rina S; Mills, Sarah D; Sadler, Georgia Robins; Malcarne, Vanessa L

    2016-01-01

    Latent profile analysis identified health locus of control profiles among 436 Hispanic Americans who completed the Multidimensional Health Locus of Control scales. Results revealed four profiles: Internally Oriented-Weak, -Moderate, -Strong, and Externally Oriented. The profile groups were compared on sociocultural and demographic characteristics, health beliefs and behaviors, and physical and mental health outcomes. The Internally Oriented-Strong group had less cancer fatalism, religiosity, and equity health attributions, and more alcohol consumption than the other three groups; the Externally Oriented group had stronger equity health attributions and less alcohol consumption. Deriving multidimensional health locus of control profiles through latent profile analysis allows examination of the relationships of health locus of control subtypes to health variables. PMID:25855212

  16. Multidimensional profiles of health locus of control in Hispanic Americans.

    PubMed

    Champagne, Brian R; Fox, Rina S; Mills, Sarah D; Sadler, Georgia Robins; Malcarne, Vanessa L

    2016-10-01

    Latent profile analysis identified health locus of control profiles among 436 Hispanic Americans who completed the Multidimensional Health Locus of Control scales. Results revealed four profiles: Internally Oriented-Weak, -Moderate, -Strong, and Externally Oriented. The profile groups were compared on sociocultural and demographic characteristics, health beliefs and behaviors, and physical and mental health outcomes. The Internally Oriented-Strong group had less cancer fatalism, religiosity, and equity health attributions, and more alcohol consumption than the other three groups; the Externally Oriented group had stronger equity health attributions and less alcohol consumption. Deriving multidimensional health locus of control profiles through latent profile analysis allows examination of the relationships of health locus of control subtypes to health variables. © The Author(s) 2015.

  17. Healthy elderly: social bonds and locus of control.

    PubMed

    Thomas, P D; Hooper, E M

    1983-03-01

    An investigation into social relationships and their connection to health was integrated into a 5-year prospective study of nutrition and immunobiology in 300 healthy elderly persons. The data were collected from a subsample of 40 individuals by interview, using the Interview Schedule for Social Interaction (ISSI), the Rotter I-E Locus of Control Scale, and the Multidimensional Health Locus of Control Scale (MHLC). This group did not differ from the general population in terms of their social relationships. The mean locus of control expectancy score was 6.5 +/- 3.3, indicating an internal group. There was a statistically significant relationship between internality and availability of social integration, but no differences based upon sex or age for the ISSI or Rotter's I-E Locus of Control Scale.

  18. Independence of Foveal Retinal Locus and Visual Detection Paradigm.

    DTIC Science & Technology

    1980-02-09

    F O-AO.. 17 ILLINOIS UNIV AT URBANA-CHAMPAIGN HUMAN ATTENTION RES -ETC F/A 5/10 INDEPENDENCE OF FOVEAL RETINAL LOCUS AND VISUAL DETECTION PARAD -ETC...variably mapped, and frame time of 100 or 200 msec for the consistent or variably mapped conditions, respectively. The main effects of experimental paradigm...Foveal Retinal Locus and Visual Detection Paradigm Walter Schneider and Arthur D. Fisk Report 8001 Human Attention Research Laboratory University of

  19. EPAct Transportation Regulatory Activities

    SciTech Connect

    2011-11-21

    The U.S. Department of Energy's (DOE) Vehicle Technologies Program manages several transportation regulatory activities established by the Energy Policy Act of 1992 (EPAct), as amended by the Energy Conservation Reauthorization Act of 1998, EPAct 2005, and the Energy Independence and Security Act of 2007 (EISA).

  20. OAR Regulatory Reform

    EPA Pesticide Factsheets

    The U.S. EPA's Office of Air and Radiation is hosting a public teleconference to solicit input on specific air and radiation actions that should be considered for “repeal, replacement, or modification” to reduce regulatory burden consistent with EO 13777.

  1. The regulatory horizon

    NASA Technical Reports Server (NTRS)

    Cook, ED

    1987-01-01

    The author briefly discusses the FAA's position as it relates to cockpit resource management. For example, if Cockpit Resource Management (CRM) is a positive concept, why isn't everyone required to implement it? The regulatory practice of the FAA is discussed and questions and answers are presented.

  2. Toxicogenomics in Regulatory Ecotoxicology

    EPA Science Inventory

    The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions, and as with any new technology, there is a wide range of opinion. The purpose of this feature article is to consider roles of toxicogenomic...

  3. Fine structure of the FMR-1 locus

    SciTech Connect

    Nelson, D.L.; Eichler, E.E.; Richards, S.; Gibbs, R.A.

    1994-07-15

    The fragile X syndrome is due to a CGG triplet expansion in the first exon of FMR-1, resulting in hypermethylation and extinction of gene expression. To further understanding of the gene`s involvement in the syndrome, we have determined the physical structure of this locus. A high resolution restriction map of cosmids from the region has been prepared encompassing approximately 50 kb. Using exon-exon PCR and restriction analysis, the FMR-1 gene has been determined to consist of 17 exons spanning 38 kb of Xq27.3. Each intron-exon boundary has been sequenced. In general, the splice donors and acceptors located in the 5{prime} portion of the gene demonstrate greater adherence to consensus than those in the 3{prime} end, providing a possible explanation for the finding of alternative splicing in FMR-1. Sequence analysis of the region immediately flanking the CGG triplet repeat demonstrated both tetranucleotide and dinucleotide repeats. Additional sequence is being obtained from the overlapping cosmids spanning the gene, and extending 20 kb proximal and approximately 30 kb distal as part of a larger project to determine sequence on the megabase scale in the Xq27.3-q28 region. These sequences are being characterized from normal and affected individuals to assess polymorphisms and the role (if any) of peculiar sequences in the generation of fragile X CGG instability. The elucidation of the structure and composition of the FMR-1 gene as well as its flanking region will enhance detection of other mutations possible in fragile X phenocopy individuals.

  4. [Health locus of control of patients in disease management programmes].

    PubMed

    Schnee, M; Grikscheit, F

    2013-06-01

    Health locus of control beliefs plays a major role in improving self-management skills of the chronically ill - a main goal in disease management programmes (DMP). This study aims at characterising participants in disease management regarding their health locus of control. Data are based on 4 cross-sectional postal surveys between spring and autumn of 2006 and 2007 within the Health Care Monitor of the Bertelsmann Foundation. Among the 6 285 respondents, 1 266 are chronically ill and not enrolled in a DMP and 327 are participating in a DMP. A high internal locus of control (HLC) occurs significantly less often in DMP patients than in normal chronically ill patients (and healthy people) controlling for age, gender and social class. With increasing age, a high internal locus of control is also significantly less likely. When comparing healthy people, the chronically ill and the DMP participants a social gradient of a high internal locus of control belief can be observed. The weaker internal and higher doctor-related external locus of control of DMP participants should be carefully observed by the physician when trying to strengthen the patients' self-management skills. Evaluators of DMP should take into account the different baselines of DMP patients and relevant control groups and incorporate these differences into the evaluation. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Strategies for conditional two-locus nonparametric linkage analysis.

    PubMed

    Angquist, Lars; Hössjer, Ola; Groop, Leif

    2008-01-01

    In this article we deal with two-locus nonparametric linkage (NPL) analysis, mainly in the context of conditional analysis. This means that one incorporates single-locus analysis information through conditioning when performing a two-locus analysis. Here we describe different strategies for using this approach. Cox et al. [Nat Genet 1999;21:213-215] implemented this as follows: (i) Calculate the one-locus NPL process over the included genome region(s). (ii) Weight the individual pedigree NPL scores using a weighting function depending on the NPL scores for the corresponding pedigrees at speci fi c conditioning loci. We generalize this by conditioning with respect to the inheritance vector rather than the NPL score and by separating between the case of known (prede fi ned) and unknown (estimated) conditioning loci. In the latter case we choose conditioning locus, or loci, according to prede fi ned criteria. The most general approach results in a random number of selected loci, depending on the results from the previous one-locus analysis. Major topics in this article include discussions on optimal score functions with respect to the noncentrality parameter (NCP), and how to calculate adequate p values and perform power calculations. We also discuss issues related to multiple tests which arise from the two-step procedure with several conditioning loci as well as from the