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Sample records for imprinted gene snurf

  1. [Imprinted genes in plants].

    PubMed

    Zhang, Li-Geng; Yang, Ruo-Fei; Fu, Feng-Ling; Li, Wan-Chen

    2010-12-01

    The expression of imprinted genes is regulated by epigenetic mechanism. In plant endosperm, the allele of imprinted genes is expressed in a pattern of parent-of-origin-dependent. The expression of imprinted genes plays essential roles in the development of embryos and their annexe structures, as well as seed size, reproductive barriers and apomixis. Along with the progress of plant epigenetic research, the exploration of imprinted genes is becoming hotspot in epigenetic research. This review focused on the parental conflict theory about the origin of imprinted genes, and the latest research advances in expression regulation mechanism of plant imprinted genes, using the examples of the important imprinted genes MEA, FIS2, FWA, MPC, and PHE1 in Arabidopsis, and FIEI and FIE2 in maize. PMID:21513148

  2. The imprinted SNRPN gene is associated with a polycistronic mRNA and an imprinting control element

    SciTech Connect

    Saitoh, S.; Nicholls, R.D.; Seip, J.

    1994-09-01

    The small nuclear ribonucleoprotein-associated protein SmN (SNRPN) gene is located in the Prader-Willi syndrome (PWS) critical region in chromosome 15q11-q13. We have previously shown that it is functionally imprinted in humans, being only expressed from the paternal allele and differentially methylated on parental alleles. Therefore, SNRPN may have a role in PWS, although genetic studies suggest that at least two genes may be necessary for the classical PWS phenotype. We have characterized the SNRPN genomic structure, and shown that it comprises ten exons. Surprisingly, we identified an open reading frame (ORF) in the first three exons, 190-bp 5{prime} to the SmN ORF. Notably, the majority of base substitutions bewteen human and rodents in the upstream ORF occurred in the wobble position of codons, suggesting selection for a protein coding function. This ORF, which we name SNURF (SNRPN upstream reading frame) encodes a putative polypeptide of 71 amino acids. By analogy to prokaryotic operons that encode proteins with related functions, it is possible that SNURF may have a role in pre-mRNA splicing.

  3. Imprinting genes associated with endometriosis

    PubMed Central

    Kobayashi, Hiroshi

    2014-01-01

    Purpose: Much work has been carried out to investigate the genetic and epigenetic basis of endometriosis and proposed that endometriosis has been described as an epigenetic disease. The purpose of this study was to extract the imprinting genes that are associated with endometriosis development. Methods: The information on the imprinting genes can be accessed publicly from a web-based interface at http://www.geneimprint.com/site/genes-by-species. Results: In the current version, the database contains 150 human imprinted genes derived from the literature. We searched gene functions and their roles in particular biological processes or events, such as development and pathogenesis of endometriosis. From the genomic imprinting database, we picked 10 genes that were highly associated with female reproduction; prominent among them were paternally expressed genes (DIRAS3, BMP8B, CYP1B1, ZFAT, IGF2, MIMT1, or MIR296) and maternally expressed genes (DVL1, FGFRL1, or CDKN1C). These imprinted genes may be associated with reproductive biology such as endometriosis, pregnancy loss, decidualization process and preeclampsia. Discussion: This study supports the possibility that aberrant epigenetic dysregulation of specific imprinting genes may contribute to endometriosis predisposition. PMID:26417259

  4. Imprinted control of gene activity in Drosophila.

    PubMed

    Golic, K G; Golic, M M; Pimpinelli, S

    1998-11-19

    Genetic imprinting is defined as a reversible, differential marking of genes or chromosomes that is determined by the sex of the parent from whom the genetic material is inherited [1]. Imprinting was first observed in insects where, in some species, most notably among the coccoids (scale insects and allies), the differential marking of paternally and maternally transmitted chromosome sets leads to inactivation or elimination of paternal chromosomes [2]. Imprinting is also widespread in plants and mammals [3,4], in which paternally and maternally inherited alleles may be differentially expressed. Despite imprinting having been discovered in insects, clear examples of parental imprinting are scarce in the model insect species Drosophila melanogaster. We describe a case of imprint-mediated control of gene expression in Drosophila. The imprinted gene - the white+ eye-color gene - is expressed at a low level when transmitted by males, and at a high level when transmitted by females. Thus, in common with coccoids, Drosophila is capable of generating an imprint, and can respond to that imprint by silencing the paternal allele. PMID:9822579

  5. The role of imprinted genes in humans.

    PubMed

    Ishida, Miho; Moore, Gudrun E

    2013-01-01

    Genomic imprinting, a process of epigenetic modification which allows the gene to be expressed in a parent-of-origin specific manner, has an essential role in normal growth and development. Imprinting is found predominantly in placental mammals, and has potentially evolved as a mechanism to balance parental resource allocation to the offspring. Therefore, genetic and epigenetic disruptions which alter the specific dosage of imprinted genes can lead to various developmental abnormalities often associated with fetal growth and neurological behaviour. Over the past 20 years since the first imprinted gene was discovered, many different mechanisms have been implicated in this special regulatory mode of gene expression. This review includes a brief summary of the current understanding of the key molecular events taking place during imprint establishment and maintenance in early embryos, and their relationship to epigenetic disruptions seen in imprinting disorders. Genetic and epigenetic causes of eight recognised imprinting disorders including Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS), and also their association with Assisted reproductive technology (ART) will be discussed. Finally, the role of imprinted genes in fetal growth will be explored by investigating their relationship to a common growth disorder, intrauterine growth restriction (IUGR) and also their potential role in regulating normal growth variation. PMID:22771538

  6. Sexual differences of imprinted genes' expression levels.

    PubMed

    Faisal, Mohammad; Kim, Hana; Kim, Joomyeong

    2014-01-01

    In mammals, genomic imprinting has evolved as a dosage-controlling mechanism for a subset of genes that play critical roles in their unusual reproduction scheme involving viviparity and placentation. As such, many imprinted genes are highly expressed in sex-specific reproductive organs. In the current study, we sought to test whether imprinted genes are differentially expressed between the two sexes. According to the results, the expression levels of the following genes differ between the two sexes of mice: Peg3, Zim1, Igf2, H19 and Zac1. The expression levels of these imprinted genes are usually greater in males than in females. This bias is most obvious in the developing brains of 14.5-dpc embryos, but also detected in the brains of postnatal-stage mice. However, this sexual bias is not obvious in 10.5-dpc embryos, a developmental stage before the sexual differentiation. Thus, the sexual bias observed in the imprinted genes is most likely attributable by gonadal hormones rather than by sex chromosome complement. Overall, the results indicate that several imprinted genes are sexually different in terms of their expression levels, and further suggest that the transcriptional regulation of these imprinted genes may be influenced by unknown mechanisms associated with sexual differentiation. PMID:24125951

  7. Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

    PubMed Central

    Izzi, Benedetta; Francois, Inge; Labarque, Veerle; Thys, Chantal; Wittevrongel, Christine; Devriendt, Koen; Legius, Eric; Van den Bruel, Annick; D'Hooghe, Marc; Lambrechts, Diether; de Zegher, Francis; Van Geet, Chris; Freson, Kathleen

    2012-01-01

    Background Pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene. PHP-Ib patients have isolated Parathormone (PTH) resistance and GNAS epigenetic defects while PHP-Ia cases present with hormone resistance and characteristic features jointly termed as Albright's Hereditary Osteodystrophy (AHO) due to maternally inherited GNAS mutations or similar epigenetic defects as found for PHP-Ib. Pseudopseudohypoparathyroidism (PPHP) patients with an AHO phenotype and no hormone resistance and progressive osseous heteroplasia (POH) cases have inactivating paternally inherited GNAS mutations. Methodology/Principal Findings We here describe 17 subjects with an AHO-like phenotype that could be compatible with having PPHP but none of them carried Gsalpha mutations. Functional platelet studies however showed an obvious Gs hypofunction in the 13 patients that were available for testing. Methylation for the three differentially methylated GNAS regions was quantified via the Sequenom EpiTYPER. Patients showed significant hypermethylation of the XL amplicon compared to controls (36±3 vs. 29±3%; p<0.001); a pattern that is reversed to XL hypomethylation found in PHPIb. Interestingly, XL hypermethylation was associated with reduced XLalphaS protein levels in the patients' platelets. Methylation for NESP and ExonA/B was significantly different for some but not all patients, though most patients have site-specific CpG methylation abnormalities in these amplicons. Since some AHO features are present in other imprinting disorders, the methylation of IGF2, H19, SNURF and GRB10 was quantified. Surprisingly, significant IGF2 hypermethylation (20±10 vs. 14±7%; p<0.05) and SNURF hypomethylation (23±6 vs. 32±6%; p<0.001) was found in patients vs. controls, while H19 and GRB10 methylation was normal. Conclusion/Significance In conclusion, this

  8. Roles of imprinted genes in neural stem cells.

    PubMed

    Hoffmann, Anke; Daniel, Guillaume; Schmidt-Edelkraut, Udo; Spengler, Dietmar

    2014-01-01

    Imprinted genes and neural stem cells (NSC) play an important role in the developing and mature brain. A central theme of imprinted gene function in NSCs is cell survival and G1 arrest to control cell division, cell-cycle exit, migration and differentiation. Moreover, genomic imprinting can be epigenetically switched off at some genes to ensure stem cell quiescence and differentiation. At the genome scale, imprinted genes are organized in dynamic networks formed by interchromosomal interactions and transcriptional coregulation of imprinted and nonimprinted genes. Such multilayered networks may synchronize NSC activity with the demand from the niche resembling their roles in adjusting fetal size. PMID:25431944

  9. Comprehensive analysis of imprinted genes in maize reveals allelic variation for imprinting and limited conservation with other species.

    PubMed

    Waters, Amanda J; Bilinski, Paul; Eichten, Steven R; Vaughn, Matthew W; Ross-Ibarra, Jeffrey; Gehring, Mary; Springer, Nathan M

    2013-11-26

    In plants, a subset of genes exhibit imprinting in endosperm tissue such that expression is primarily from the maternal or paternal allele. Imprinting may arise as a consequence of mechanisms for silencing of transposons during reproduction, and in some cases imprinted expression of particular genes may provide a selective advantage such that it is conserved across species. Separate mechanisms for the origin of imprinted expression patterns and maintenance of these patterns may result in substantial variation in the targets of imprinting in different species. Here we present deep sequencing of RNAs isolated from reciprocal crosses of four diverse maize genotypes, providing a comprehensive analysis that allows evaluation of imprinting at more than 95% of endosperm-expressed genes. We find that over 500 genes exhibit statistically significant parent-of-origin effects in maize endosperm tissue, but focused our analyses on a subset of these genes that had >90% expression from the maternal allele (69 genes) or from the paternal allele (108 genes) in at least one reciprocal cross. Over 10% of imprinted genes show evidence of allelic variation for imprinting. A comparison of imprinting in maize and rice reveals that 13% of genes with syntenic orthologs in both species exhibit conserved imprinting. Genes that exhibit conserved imprinting between maize and rice have elevated nonsynonymous to synonymous substitution ratios compared with other imprinted genes, suggesting a history of more rapid evolution. Together, these data suggest that imprinting only has functional relevance at a subset of loci that currently exhibit imprinting in maize. PMID:24218619

  10. Regulatory links between imprinted genes: evolutionary predictions and consequences

    PubMed Central

    Patten, Manus M.; Cowley, Michael; Oakey, Rebecca J.; Feil, Robert

    2016-01-01

    Genomic imprinting is essential for development and growth and plays diverse roles in physiology and behaviour. Imprinted genes have traditionally been studied in isolation or in clusters with respect to cis-acting modes of gene regulation, both from a mechanistic and evolutionary point of view. Recent studies in mammals, however, reveal that imprinted genes are often co-regulated and are part of a gene network involved in the control of cellular proliferation and differentiation. Moreover, a subset of imprinted genes acts in trans on the expression of other imprinted genes. Numerous studies have modulated levels of imprinted gene expression to explore phenotypic and gene regulatory consequences. Increasingly, the applied genome-wide approaches highlight how perturbation of one imprinted gene may affect other maternally or paternally expressed genes. Here, we discuss these novel findings and consider evolutionary theories that offer a rationale for such intricate interactions among imprinted genes. An evolutionary view of these trans-regulatory effects provides a novel interpretation of the logic of gene networks within species and has implications for the origin of reproductive isolation between species. PMID:26842569

  11. Genome-wide prediction of imprinted murine genes

    PubMed Central

    Luedi, Philippe P.; Hartemink, Alexander J.; Jirtle, Randy L.

    2005-01-01

    Imprinted genes are epigenetically modified genes whose expression is determined according to their parent of origin. They are involved in embryonic development, and imprinting dysregulation is linked to cancer, obesity, diabetes, and behavioral disorders such as autism and bipolar disease. Herein, we train a statistical model based on DNA sequence characteristics that not only identifies potentially imprinted genes, but also predicts the parental allele from which they are expressed. Of 23,788 annotated autosomal mouse genes, our model identifies 600 (2.5%) to be potentially imprinted, 64% of which are predicted to exhibit maternal expression. These predictions allowed for the identification of putative candidate genes for complex conditions where parent-of-origin effects are involved, including Alzheimer disease, autism, bipolar disorder, diabetes, male sexual orientation, obesity, and schizophrenia. We observe that the number, type, and relative orientation of repeated elements flanking a gene are particularly important in predicting whether a gene is imprinted. PMID:15930497

  12. Characterization of Conserved and Nonconserved Imprinted Genes in Swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic imprinting results in the silencing of a subset of mammalian alleles due to parent-of-origin inheritance. Due to the nature of their expression patterns they play a critical role in placental and early embryonic development. In order to increase our understanding of imprinted genes specifi...

  13. Imprinted genes as potential genetic and epigenetic toxicologic targets.

    PubMed Central

    Murphy, S K; Jirtle, R L

    2000-01-01

    Genomic imprinting is an epigenetic phenomenon in eutherian mammals that results in the differential expression of the paternally and maternally inherited alleles of a gene. Imprinted genes are necessary for normal mammalian development. This requirement has been proposed to have evolved because of an interparental genetic battle for the utilization of maternal resources during gestation and postnatally. The nonrandom requisite for monoallelic expression of a subset of genes has also resulted in the formation of susceptibility loci for neurobehavioral disorders, developmental disorders, and cancer. Since imprinting involves both cytosine methylation within CpG islands and changes in chromatin structure, imprinted genes are potential targets for dysregulation by epigenetic toxicants that modify DNA methylation and histone acetylation. PMID:10698719

  14. The Imprinted Gene DIO3 Is a Candidate Gene for Litter Size in Pigs

    PubMed Central

    Coster, Albart; Madsen, Ole; Heuven, Henri C. M.; Dibbits, Bert; Groenen, Martien A. M.; van Arendonk, Johan A. M.; Bovenhuis, Henk

    2012-01-01

    Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant () additive and dominant effects and one SNP showed a significant imprinting effect. The SNP with a significant imprinting effect is closely linked to DIO3, a gene involved in thyroid metabolism. The imprinting effect of this SNP explained approximately 1.6% of the phenotypic variance, which corresponded to approximately 15.5% of the additive genetic variance. In the other population, the imprinting effect of this QTL was not significant (), but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs. PMID:22393372

  15. Cell Pluripotency Levels Associated with Imprinted Genes in Human

    PubMed Central

    Yuan, Liyun; Tang, Xiaoyan; Zhang, Binyan; Ding, Guohui

    2015-01-01

    Pluripotent stem cells are exhibited similarly in the morphology, gene expression, growth properties, and epigenetic modification with embryonic stem cells (ESCs). However, it is still controversial that the pluripotency of induced pluripotent stem cell (iPSC) is much inferior to ESC, and the differentiation capacity of iPSC and ESC can also be separated by transcriptome and epigenetics. miRNAs, which act in posttranscriptional regulation of gene expression and are involved in many basic cellular processes, may reveal the answer. In this paper, we focused on identifying the hidden relationship between miRNAs and imprinted genes in cell pluripotency. Total miRNA expression patterns in iPSC and ES cells were comprehensively analysed and linked with human imprinted genes, which show a global picture of their potential function in pluripotent level. A new CPA4-KLF14 region which locates in chromosomal homologous segments (CHSs) within mammals and include both imprinted genes and significantly expressed miRNAs was first identified. Molecular network analysis showed genes interacted with imprinted genes closely and enriched in modules such as cancer, cell death and survival, and tumor morphology. This imprinted region may provide a new look for those who are interested in cell pluripotency of hiPSCs and hESCs. PMID:26504487

  16. Cell Pluripotency Levels Associated with Imprinted Genes in Human.

    PubMed

    Yuan, Liyun; Tang, Xiaoyan; Zhang, Binyan; Ding, Guohui

    2015-01-01

    Pluripotent stem cells are exhibited similarly in the morphology, gene expression, growth properties, and epigenetic modification with embryonic stem cells (ESCs). However, it is still controversial that the pluripotency of induced pluripotent stem cell (iPSC) is much inferior to ESC, and the differentiation capacity of iPSC and ESC can also be separated by transcriptome and epigenetics. miRNAs, which act in posttranscriptional regulation of gene expression and are involved in many basic cellular processes, may reveal the answer. In this paper, we focused on identifying the hidden relationship between miRNAs and imprinted genes in cell pluripotency. Total miRNA expression patterns in iPSC and ES cells were comprehensively analysed and linked with human imprinted genes, which show a global picture of their potential function in pluripotent level. A new CPA4-KLF14 region which locates in chromosomal homologous segments (CHSs) within mammals and include both imprinted genes and significantly expressed miRNAs was first identified. Molecular network analysis showed genes interacted with imprinted genes closely and enriched in modules such as cancer, cell death and survival, and tumor morphology. This imprinted region may provide a new look for those who are interested in cell pluripotency of hiPSCs and hESCs. PMID:26504487

  17. Expression and genomic imprinting of the porcine Rasgrf1 gene.

    PubMed

    Ding, Yue-Yun; Liu, Li-Yuan; Zhou, Jie; Zhang, Xiao-Dong; Huang, Long; Zhang, Shu-Jing; Yin, Zong-Jun

    2014-02-25

    Imprinted genes play important roles in mammalian growth, development and behavior. The Rasgrf1 (Ras protein-specific guanine nucleotide exchange factor 1) gene has been identified as an imprinted gene in mouse and rat. In the present study, we detected its sequence, imprinting status and expression pattern in the domestic pigs. A 228 bp partial sequence located in exon 14 and a 193 bp partial sequence located in exon 1 of the Rasgrf1 gene in domestic pigs were obtained. A G/A transition, was identified in Rasgrf1 exon 14, and then, the reciprocal Berkshire × Wannan black F1 hybrid model and the RT-PCR-RFLP method were used to detect the imprinting status of porcine Rasgrf1 gene at the developmental stage of 1-day-old. The expression profile results indicated that the porcine Rasgrf1 mRNA was highly expressed in brain, pituitary and pancreas, followed by kidney, stomach, lung, testis, small intestine, ovary, spleen and liver, and at low levels of expression in longissimus dorsi, heart, and backfat. The expression levels of Rasgrf1 gene in brain, pituitary and pancreas tissues were significantly different between the two reciprocal F1 hybrids. Imprinting analysis showed that porcine Rasgrf1 gene was maternally expressed in the liver, small intestine, paternally expressed in the lung, but biallelically expressed in brain, heart, spleen, kidney, stomach, pancreas, backfat, testis, ovary, longissimus dorsi and pituitary tissues. PMID:24342659

  18. Gene interactions in the evolution of genomic imprinting.

    PubMed

    Wolf, J B; Brandvain, Y

    2014-08-01

    Numerous evolutionary theories have been developed to explain the epigenetic phenomenon of genomic imprinting. Here, we explore a subset of theories wherein non-additive genetic interactions can favour imprinting. In the simplest genic interaction--the case of underdominance--imprinting can be favoured to hide effectively low-fitness heterozygous genotypes; however, as there is no asymmetry between maternally and paternally inherited alleles in this model, other means of enforcing monoallelic expression may be more plausible evolutionary outcomes than genomic imprinting. By contrast, more successful interaction models of imprinting rely on an asymmetry between the maternally and paternally inherited alleles at a locus that favours the silencing of one allele as a means of coordinating the expression of high-fitness allelic combinations. For example, with interactions between autosomal loci, imprinting functionally preserves high-fitness genotypes that were favoured by selection in the previous generation. In this scenario, once a focal locus becomes imprinted, selection at interacting loci favours a matching imprint. Uniparental transmission generates similar asymmetries for sex chromosomes and cytoplasmic factors interacting with autosomal loci, with selection favouring the expression of either maternal or paternally derived autosomal alleles depending on the pattern of transmission of the uniparentally inherited factor. In a final class of models, asymmetries arise when genes expressed in offspring interact with genes expressed in one of its parents. Under such a scenario, a locus evolves to have imprinted expression in offspring to coordinate the interaction with its parent's genome. We illustrate these models and explore key links and differences using a unified framework. PMID:24619179

  19. Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes

    PubMed Central

    Higashiura, Yumi; Koike, Natsuki; Akasaka, Juria; Uekuri, Chiharu; Iwai, Kana; Niiro, Emiko; Morioka, Sachiko; Yamada, Yuki

    2014-01-01

    There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes. PMID:24615936

  20. A Survey of Imprinted Gene Expression in Mouse Trophoblast Stem Cells

    PubMed Central

    Calabrese, J. Mauro; Starmer, Joshua; Schertzer, Megan D.; Yee, Della; Magnuson, Terry

    2015-01-01

    Several hundred mammalian genes are expressed preferentially from one parental allele as the result of a process called genomic imprinting. Genomic imprinting is prevalent in extra-embryonic tissue, where it plays an essential role during development. Here, we profiled imprinted gene expression via RNA-Seq in a panel of six mouse trophoblast stem lines, which are ex vivo derivatives of a progenitor population that gives rise to the placental tissue of the mouse. We found evidence of imprinted expression for 48 genes, 31 of which had been described previously as imprinted and 17 of which we suggest as candidate imprinted genes. An equal number of maternally and paternally biased genes were detected. On average, candidate imprinted genes were more lowly expressed and had weaker parent-of-origin biases than known imprinted genes. Several known and candidate imprinted genes showed variability in parent-of-origin expression bias between the six trophoblast stem cell lines. Sixteen of the 48 known and candidate imprinted genes were previously or newly annotated noncoding RNAs and six encoded for a total of 60 annotated microRNAs. Pyrosequencing across our panel of trophoblast stem cell lines returned levels of imprinted expression that were concordant with RNA-Seq measurements for all eight genes examined. Our results solidify trophoblast stem cells as a cell culture-based experimental model to study genomic imprinting, and provide a quantitative foundation upon which to delineate mechanisms by which the process is maintained in the mouse. PMID:25711832

  1. The imprinted gene DIO3 is a candidate gene for litter size in pigs.

    PubMed

    Coster, Albart; Madsen, Ole; Heuven, Henri C M; Dibbits, Bert; Groenen, Martien A M; van Arendonk, Johan A M; Bovenhuis, Henk

    2012-01-01

    Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant (q-value < 0.10) additive and dominant effects and one SNP showed a significant imprinting effect. The SNP with a significant imprinting effect is closely linked to DIO3, a gene involved in thyroid metabolism. The imprinting effect of this SNP explained approximately 1.6% of the phenotypic variance, which corresponded to approximately 15.5% of the additive genetic variance. In the other population, the imprinting effect of this QTL was not significant (q-value > 0.10), but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs. PMID:22393372

  2. Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting

    PubMed Central

    Pignatta, Daniela; Erdmann, Robert M; Scheer, Elias; Picard, Colette L; Bell, George W; Gehring, Mary

    2014-01-01

    Imprinted gene expression occurs during seed development in plants and is associated with differential DNA methylation of parental alleles, particularly at proximal transposable elements (TEs). Imprinting variability could contribute to observed parent-of-origin effects on seed development. We investigated intraspecific variation in imprinting, coupled with analysis of DNA methylation and small RNAs, among three Arabidopsis strains with diverse seed phenotypes. The majority of imprinted genes were parentally biased in the same manner among all strains. However, we identified several examples of allele-specific imprinting correlated with intraspecific epigenetic variation at a TE. We successfully predicted imprinting in additional strains based on methylation variability. We conclude that there is standing variation in imprinting even in recently diverged genotypes due to intraspecific epiallelic variation. Our data demonstrate that epiallelic variation and genomic imprinting intersect to produce novel gene expression patterns in seeds. DOI: http://dx.doi.org/10.7554/eLife.03198.001 PMID:24994762

  3. Identification and Epigenetic Analysis of a Maternally Imprinted Gene Qpct

    PubMed Central

    Guo, Jing; He, Hongjuan; Liu, Qi; Zhang, Fengwei; Lv, Jie; Zeng, Tiebo; Gu, Ning; Wu, Qiong

    2015-01-01

    Most imprinted genes are concerned with embryonic development, especially placental development. Here, we identified a placenta-specific imprinted gene Qpct. Our results show that Qpct is widely expressed during early embryonic development and can be detected in the telecephalon, midbrain, and rhombencephalon at E9.5–E11.5. Moreover, Qpct is strikingly expressed in the brain, lung and liver in E15.5. Expression signals for Qpct achieved a peak at E15.5 during placental development and were only detected in the labyrinth layer in E15.5 placenta. ChIP assay results suggest that the modification of histone H3K4me3 can result in maternal activating of Qpct. PMID:26447138

  4. Transcriptional Profiles of Imprinted Genes in Human Embryonic Stem Cells During In vitro Differentiation

    PubMed Central

    Park, Sang-Wook; Do, Hyo-Sang; Kim, Dongkyu; Ko, Ji-Yun; Lee, Sang-Hun; Han, Yong-Mahn

    2014-01-01

    Background and Objectives: Genomic imprinting is an inheritance phenomenon by which a subset of genes are expressed from one allele of two homologous chromosomes in a parent of origin-specific manner. Even though fine-tuned regulation of genomic imprinting process is essential for normal development, no other means are available to study genomic imprinting in human during embryonic development. In relation with this bottleneck, differentiation of human embryonic stem cells (hESCs) into specialized lineages may be considered as an alternative to mimic human development. Methods and Results: In this study, hESCs were differentiated into three lineage cell types to analyze temporal and spatial expression of imprinted genes. Of 19 imprinted genes examined, 15 imprinted genes showed similar transcriptional level among two hESC lines and two human induced pluripotent stem cell (hiPSC) lines. Expressional patterns of most imprinted genes were varied in progenitors and fully differentiated cells which were derived from hESCs. Also, no consistence was observed in the expression pattern of imprinted genes within an imprinting domain during in vitro differentiation of hESCs into three lineage cell types. Conclusions: Transcriptional expression of imprinted genes is regulated in a cell type- specific manner in hESCs during in vitro differentiation. PMID:25473448

  5. A Mouse Model for Imprinting of the Human Retinoblastoma Gene

    PubMed Central

    Tasiou, Vasiliki; Hiber, Michaela; Steenpass, Laura

    2015-01-01

    The human RB1 gene is imprinted due to integration of the PPP1R26P1 pseudogene into intron 2. PPP1R26P1 harbors the gametic differentially methylated region of the RB1 gene, CpG85, which is methylated in the female germ line. The paternally unmethylated CpG85 acts as promoter for the alternative transcript 2B of RB1, which interferes with expression of full-length RB1 in cis. In mice, PPP1R26P1 is not present in the Rb1 gene and Rb1 is not imprinted. Assuming that the mechanisms responsible for genomic imprinting are conserved, we investigated if imprinting of mouse Rb1 can be induced by transferring human PPP1R26P1 into mouse Rb1. We generated humanized Rb1_PPP1R26P1 knock-in mice that pass human PPP1R26P1 through the mouse germ line. We found that the function of unmethylated CpG85 as promoter for an alternative Rb1 transcript and as cis-repressor of the main Rb1 transcript is maintained in mouse tissues. However, CpG85 is not recognized as a gametic differentially methylated region in the mouse germ line. DNA methylation at CpG85 is acquired only in tissues of neuroectodermal origin, independent of parental transmission of PPP1R26P1. Absence of CpG85 methylation in oocytes and sperm implies a failure of imprint methylation establishment in the germ line. Our results indicate that site-specific integration of a proven human gametic differentially methylated region is not sufficient for acquisition of DNA methylation in the mouse germ line, even if promoter function of the element is maintained. This suggests a considerable dependency of DNA methylation induction on the surrounding sequence. However, our model is suited to determine the cellular function of the alternative Rb1 transcript. PMID:26275142

  6. Allelic expression of mammalian imprinted genes in a matrotrophic lizard, Pseudemoia entrecasteauxii.

    PubMed

    Griffith, Oliver W; Brandley, Matthew C; Belov, Katherine; Thompson, Michael B

    2016-03-01

    Genomic imprinting is a process that results in the differential expression of genes depending on their parent of origin. It occurs in both plants and live-bearing mammals, with imprinted genes typically regulating the ability of an embryo to manipulate the maternal provision of nutrients. Genomic imprinting increases the potential for selection to act separately on paternally and maternally expressed genes, which increases the number of opportunities that selection can facilitate embryonic control over maternal nutrient provision. By looking for imprinting in an independent matrotrophic lineage, the viviparous lizard Pseudemoia entrecasteauxii (Scincidae), we test the hypothesis that genomic imprinting facilitates the evolution of substantial placental nutrient transport to embryos (matrotrophy). We sequenced transcriptomes from the embryonic component of lizard placentae to determine whether there are parent-of-origin differences in expression of genes that are imprinted in mammals. Of these genes, 19 had sufficiently high expression in the lizard to identify polymorphisms in transcribed sequences. We identified bi-allelic expression in 17 genes (including insulin-like growth factor 2), indicating that neither allele was imprinted. These data suggest that either genomic imprinting has not evolved in this matrotrophic skink or, if it has, it has evolved in different genes to mammals. We outline how these hypotheses can be tested. This study highlights important differences between mammalian and reptile pregnancy and the absence of any shared imprinting genes reflects fundamental differences in the way that pregnancy has evolved in these two lineages. PMID:26943808

  7. Cellular functions of genetically imprinted genes in human and mouse as annotated in the gene ontology.

    PubMed

    Hamed, Mohamed; Ismael, Siba; Paulsen, Martina; Helms, Volkhard

    2012-01-01

    By analyzing the cellular functions of genetically imprinted genes as annotated in the Gene Ontology for human and mouse, we found that imprinted genes are often involved in developmental, transport and regulatory processes. In the human, paternally expressed genes are enriched in GO terms related to the development of organs and of anatomical structures. In the mouse, maternally expressed genes regulate cation transport as well as G-protein signaling processes. Furthermore, we investigated if imprinted genes are regulated by common transcription factors. We identified 25 TF families that showed an enrichment of binding sites in the set of imprinted genes in human and 40 TF families in mouse. In general, maternally and paternally expressed genes are not regulated by different transcription factors. The genes Nnat, Klf14, Blcap, Gnas and Ube3a contribute most to the enrichment of TF families. In the mouse, genes that are maternally expressed in placenta are enriched for AP1 binding sites. In the human, we found that these genes possessed binding sites for both, AP1 and SP1. PMID:23226257

  8. Transcriptional Truncation of the Long Coding Imprinted Gene Usp29

    PubMed Central

    He, Hongzhi; Ye, An; Kim, Joomyeong

    2016-01-01

    Usp29 (Ubiquitin-specific protease 29) is a paternally expressed gene located upstream of another imprinted gene Peg3. In the current study, the transcription of this long coding gene spanning a 250-kb genomic distance was truncated using a knockin allele. According to the results, paternal transmission of the mutant allele resulted in reduced body and litter sizes whereas the maternal transmission caused no obvious effects. In the paternal mutant, the expression levels of Usp29 were reduced to 14–18% level of the wild-type littermates due to the Poly-A signal included in the knockin cassette. Expression analyses further revealed an unusual female-specific up-regulation of the adjacent imprinted gene Zfp264 in the mutant. Consistent with this, the promoter of Zfp264 was hypomethylated only in the female mutant. Interestingly, this female-specific hypomethylation by the knockin allele was not detected in the offspring of an interspecific crossing, indicating its sensitivity to genetic background. Overall, the results suggest that the transcription of Usp29 may be involved in DNA methylation setting of Zfp264 promoter in a sex-specific manner. PMID:27327533

  9. Global assessment of imprinted gene expression in the bovine conceptus by next generation sequencing

    PubMed Central

    Chen, Zhiyuan; Hagen, Darren E.; Wang, Juanbin; Elsik, Christine G.; Ji, Tieming; Siqueira, Luiz G.; Hansen, Peter J.; Rivera, Rocío M.

    2016-01-01

    ABSTRACT Genomic imprinting is an epigenetic mechanism that leads to parental-allele-specific gene expression. Approximately 150 imprinted genes have been identified in humans and mice but less than 30 have been described as imprinted in cattle. For the purpose of de novo identification of imprinted genes in bovine, we determined global monoallelic gene expression in brain, skeletal muscle, liver, kidney and placenta of day ∼105 Bos taurus indicus × Bos taurus taurus F1 conceptuses using RNA sequencing. To accomplish this, we developed a bioinformatics pipeline to identify parent-specific single nucleotide polymorphism alleles after filtering adenosine to inosine (A-to-I) RNA editing sites. We identified 53 genes subject to monoallelic expression. Twenty three are genes known to be imprinted in the cow and an additional 7 have previously been characterized as imprinted in human and/or mouse that have not been reported as imprinted in cattle. Of the remaining 23 genes, we found that 10 are uncharacterized or unannotated transcripts located in known imprinted clusters, whereas the other 13 genes are distributed throughout the bovine genome and are not close to any known imprinted clusters. To exclude potential cis-eQTL effects on allele expression, we corroborated the parental specificity of monoallelic expression in day 86 Bos taurus taurus × Bos taurus taurus conceptuses and identified 8 novel bovine imprinted genes. Further, we identified 671 candidate A-to-I RNA editing sites and describe random X-inactivation in day 15 bovine extraembryonic membranes. Our results expand the imprinted gene list in bovine and demonstrate that monoallelic gene expression can be the result of cis-eQTL effects. PMID:27245094

  10. Global assessment of imprinted gene expression in the bovine conceptus by next generation sequencing.

    PubMed

    Chen, Zhiyuan; Hagen, Darren E; Wang, Juanbin; Elsik, Christine G; Ji, Tieming; Siqueira, Luiz G; Hansen, Peter J; Rivera, Rocío M

    2016-07-01

    Genomic imprinting is an epigenetic mechanism that leads to parental-allele-specific gene expression. Approximately 150 imprinted genes have been identified in humans and mice but less than 30 have been described as imprinted in cattle. For the purpose of de novo identification of imprinted genes in bovine, we determined global monoallelic gene expression in brain, skeletal muscle, liver, kidney and placenta of day ∼105 Bos taurus indicus × Bos taurus taurus F1 conceptuses using RNA sequencing. To accomplish this, we developed a bioinformatics pipeline to identify parent-specific single nucleotide polymorphism alleles after filtering adenosine to inosine (A-to-I) RNA editing sites. We identified 53 genes subject to monoallelic expression. Twenty three are genes known to be imprinted in the cow and an additional 7 have previously been characterized as imprinted in human and/or mouse that have not been reported as imprinted in cattle. Of the remaining 23 genes, we found that 10 are uncharacterized or unannotated transcripts located in known imprinted clusters, whereas the other 13 genes are distributed throughout the bovine genome and are not close to any known imprinted clusters. To exclude potential cis-eQTL effects on allele expression, we corroborated the parental specificity of monoallelic expression in day 86 Bos taurus taurus × Bos taurus taurus conceptuses and identified 8 novel bovine imprinted genes. Further, we identified 671 candidate A-to-I RNA editing sites and describe random X-inactivation in day 15 bovine extraembryonic membranes. Our results expand the imprinted gene list in bovine and demonstrate that monoallelic gene expression can be the result of cis-eQTL effects. PMID:27245094

  11. Brain-expressed imprinted genes and adult behaviour: the example of Nesp and Grb10.

    PubMed

    Dent, Claire L; Isles, Anthony R

    2014-02-01

    Imprinted genes are defined by their parent-of-origin-specific monoallelic expression. Although the epigenetic mechanisms regulating imprinted gene expression have been widely studied, their functional importance is still unclear. Imprinted genes are associated with a number of physiologies, including placental function and foetal growth, energy homeostasis, and brain and behaviour. This review focuses on genomic imprinting in the brain and on two imprinted genes in particular, Nesp and paternal Grb10, which, when manipulated in animals, have been shown to influence adult behaviour. These two genes are of particular interest as they are expressed in discrete and overlapping neural regions, recognised as key "imprinting hot spots" in the brain. Furthermore, these two genes do not appear to influence placental function and/or maternal provisioning of offspring. Consequently, by understanding their behavioural function we may begin to shed light on the evolutionary significance of imprinted genes in the adult brain, independent of the recognised role in maternal care. In addition, we discuss the potential future directions of research investigating the function of these two genes and the behavioural role of imprinted genes more generally. PMID:23974804

  12. Characterization of Conserved and Non-conserved Imprinted Genes in Swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to increase our understanding of the role of imprinted genes in swine reproduction we used two complementary approaches, analysis of imprinting by pyrosequencing, and expression profiling of parthenogenetic fetuses, to carry out a comprehensive analysis of this gene family in swine. Using A...

  13. Methylation Alterations at Imprinted Genes Detected Among Long Term Shiftworkers

    PubMed Central

    Jacobs, Daniel I.; Hansen, Johnni; Fu, Alan; Stevens, Richard G.; Tjonneland, Anne; Vogel, Ulla B.; Zheng, Tongzhang; Zhu, Yong

    2016-01-01

    Exposure to light at night through shiftwork has been linked to alterations in DNA methylation and increased risk of cancer development. Using an Illumina Infinium Methylation Assay, we analyzed methylation levels of 397 CpG sites in the promoter regions of 56 normally imprinted genes to investigate whether shiftwork is associated with alteration of methylation patterns. Methylation was significantly higher at 20 CpG sites and significantly lower at 30 CpG sites (P < 0.05) in 10 female long-term shiftworkers as compared to 10 female age- and folate intake-matched day workers. The strongest evidence for altered methylation patterns in shiftworkers was observed for DLX5, IGF2AS, and TP73 based on the magnitude of methylation change and consistency in the direction of change across multiple CpG sites, and consistent results were observed using quantitative DNA methylation analysis. We conclude that long-term shiftwork may alter methylation patterns at imprinted genes, which may be an important mechanism by which shiftwork has carcinogenic potential and warrants further investigation. PMID:23193016

  14. Data mining as a discovery tool for imprinted genes.

    PubMed

    Brideau, Chelsea; Soloway, Paul

    2012-01-01

    This chapter serves as an introduction to the collection of genome-wide sequence and epigenomic data, as well as the use of these data in training generalized linear models (glm) to predicted imprinted status. This is meant to be an introduction to the method, so only the most straightforward examples will be covered. For instance, the examples given below refer to 11 classes of genomic regions (the entire gene body, introns, exons, 5' UTR, 3' UTR, and 1, 10, and 100 kb upstream and downstream of each gene). One could also build models based on combinations of these regions. Likewise, models could be built on combinations of epigenetic features, or on combinations of both genomic regions and epigenetic features.This chapter relies heavily on computational methods, including basic programming. However, this chapter is not meant to be an introduction to programming. Throughout the chapter, the reader will be provided with example code in the Perl programming language. PMID:22907493

  15. High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta

    PubMed Central

    2010-01-01

    Background Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue. Results Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%). Conclusions Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term

  16. Imprinted Genes and the Environment: Links to the Toxic Metals Arsenic, Cadmium and Lead

    PubMed Central

    Smeester, Lisa; Yosim, Andrew E.; Nye, Monica D.; Hoyo, Cathrine; Murphy, Susan K.; Fry, Rebecca C.

    2014-01-01

    Imprinted genes defy rules of Mendelian genetics with their expression tied to the parent from whom each allele was inherited. They are known to play a role in various diseases/disorders including fetal growth disruption, lower birth weight, obesity, and cancer. There is increasing interest in understanding their influence on environmentally-induced disease. The environment can be thought of broadly as including chemicals present in air, water and soil, as well as food. According to the Agency for Toxic Substances and Disease Registry (ATSDR), some of the highest ranking environmental chemicals of concern include metals/metalloids such as arsenic, cadmium, and lead. The complex relationships between toxic metal exposure, imprinted gene regulation/expression and health outcomes are understudied. Herein we examine trends in imprinted gene biology, including an assessment of the imprinted genes and their known functional roles in the cell, particularly as they relate to toxic metals exposure and disease. The data highlight that many of the imprinted genes have known associations to developmental diseases and are enriched for their role in the TP53 and AhR pathways. Assessment of the promoter regions of the imprinted genes resulted in the identification of an enrichment of binding sites for two transcription factor families, namely the zinc finger family II and PLAG transcription factors. Taken together these data contribute insight into the complex relationships between toxic metals in the environment and imprinted gene biology. PMID:24921406

  17. Characterization of the differentially methylated region of the Impact gene that exhibits Glires-specific imprinting

    PubMed Central

    Okamura, Kohji; Wintle, Richard F; Scherer, Stephen W

    2008-01-01

    Background Imprinted genes are exclusively expressed from one of the two parental alleles in a parent-of-origin-specific manner. In mammals, nearly 100 genes are documented to be imprinted. To understand the mechanism behind this gene regulation and to identify novel imprinted genes, common features of DNA sequences have been analyzed; however, the general features required for genomic imprinting have not yet been identified, possibly due to variability in underlying molecular mechanisms from locus to locus. Results We performed a thorough comparative genomic analysis of a single locus, Impact, which is imprinted only in Glires (rodents and lagomorphs). The fact that Glires and primates diverged from each other as recent as 70 million years ago makes comparisons between imprinted and non-imprinted orthologues relatively reliable. In species from the Glires clade, Impact bears a differentially methylated region, whereby the maternal allele is hypermethylated. Analysis of this region demonstrated that imprinting was not associated with the presence of direct tandem repeats nor with CpG dinucleotide density. In contrast, a CpG periodicity of 8 bp was observed in this region in species of the Glires clade compared to those of carnivores, artiodactyls, and primates. Conclusions We show that tandem repeats are dispensable, establishment of the differentially methylated region does not rely on G+C content and CpG density, and the CpG periodicity of 8 bp is meaningful to the imprinting. This interval has recently been reported to be optimal for de novo methylation by the Dnmt3a-Dnmt3L complex, suggesting its importance in the establishment of imprinting in Impact and other genes. PMID:19014519

  18. Lack of imprinting of the human dopamine D4 receptor (DRD4) gene

    SciTech Connect

    Cichon, S.; Noethen, M.M.; Propping, P.; Wolf, H.K.

    1996-04-09

    The term genomic imprinting has been used to refer to the differential expression of genetic material depending on whether it has come from the male or female parent. In humans, the chromosomal region 11p15.5 has been shown to contain 2 imprinted genes (H19 and IGF2). The gene for the dopamine D4 receptor (DRD4), which is of great interest for research into neuropsychiatric disorders and psychopharmacology, is also located in this area. In the present study, we have examined the imprinting status of the DRD4 gene in brain tissue of an epileptic patient who was heterozygous for a 12 bp repeat polymorphism in exon 1 of the DRD4 gene. We show that both alleles are expressed in equivalent amounts. We therefore conclude that the DRD4 gene is not imprinted in the human brain. 30 refs., 1 fig.

  19. Critical evaluation of imprinted gene expression by RNA-Seq: a new perspective.

    PubMed

    DeVeale, Brian; van der Kooy, Derek; Babak, Tomas

    2012-01-01

    In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replication of the embryonic brain stage, where the majority of novel imprinted genes were discovered and the majority of previously known imprinted genes confirmed, resulted in only 12.9% concordance among the novel imprinted loci. Further analysis and pyrosequencing-based validation revealed that the vast majority of the novel reported imprinted loci are false-positives explained by technical and biological variation of the experimental approach. We show that allele-specific expression (ASE) measured with RNA-Seq is not accurately modeled with statistical methods that assume random independent sampling and that systematic error must be accounted for to enable accurate identification of imprinted expression. Application of a robust approach that accounts for these effects revealed 50 candidate genes where allelic bias was predicted to be parent-of-origin-dependent. However, 11 independent validation attempts through a range of allelic expression biases confirmed only 6 of these novel cases. The results emphasize the importance of independent validation and suggest that the number of imprinted genes is much closer to the initial estimates. PMID:22479196

  20. Critical Evaluation of Imprinted Gene Expression by RNA–Seq: A New Perspective

    PubMed Central

    DeVeale, Brian; van der Kooy, Derek; Babak, Tomas

    2012-01-01

    In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replication of the embryonic brain stage, where the majority of novel imprinted genes were discovered and the majority of previously known imprinted genes confirmed, resulted in only 12.9% concordance among the novel imprinted loci. Further analysis and pyrosequencing-based validation revealed that the vast majority of the novel reported imprinted loci are false-positives explained by technical and biological variation of the experimental approach. We show that allele-specific expression (ASE) measured with RNA–Seq is not accurately modeled with statistical methods that assume random independent sampling and that systematic error must be accounted for to enable accurate identification of imprinted expression. Application of a robust approach that accounts for these effects revealed 50 candidate genes where allelic bias was predicted to be parent-of-origin–dependent. However, 11 independent validation attempts through a range of allelic expression biases confirmed only 6 of these novel cases. The results emphasize the importance of independent validation and suggest that the number of imprinted genes is much closer to the initial estimates. PMID:22479196

  1. Imprinting of the MEDEA polycomb gene in the Arabidopsis endosperm.

    PubMed Central

    Kinoshita, T; Yadegari, R; Harada, J J; Goldberg, R B; Fischer, R L

    1999-01-01

    In flowering plants, two cells are fertilized in the haploid female gametophyte. Egg and sperm nuclei fuse to form the embryo. A second sperm nucleus fuses with the central cell nucleus that replicates to generate the endosperm, which is a tissue that supports embryo development. MEDEA (MEA) encodes an Arabidopsis SET domain Polycomb protein. Inheritance of a maternal loss-of-function mea allele results in embryo abortion and prolonged endosperm production, irrespective of the genotype of the paternal allele. Thus, only the maternal wild-type MEA allele is required for proper embryo and endosperm development. To understand the molecular mechanism responsible for the parent-of-origin effects of mea mutations on seed development, we compared the expression of maternal and paternal MEA alleles in the progeny of crosses between two Arabidopsis ecotypes. Only the maternal MEA mRNA was detected in the endosperm from seeds at the torpedo stage and later. By contrast, expression of both maternal and paternal MEA alleles was observed in the embryo from seeds at the torpedo stage and later, in seedling, leaf, stem, and root. Thus, MEA is an imprinted gene that displays parent-of-origin-dependent monoallelic expression specifically in the endosperm. These results suggest that the embryo abortion observed in mutant mea seeds is due, at least in part, to a defect in endosperm function. Silencing of the paternal MEA allele in the endosperm and the phenotype of mutant mea seeds supports the parental conflict theory for the evolution of imprinting in plants and mammals. PMID:10521524

  2. Effects of Gold Nanorods on Imprinted Genes Expression in TM-4 Sertoli Cells

    PubMed Central

    Yuan, Beilei; Gu, Hao; Xu, Bo; Tang, Qiuqin; Wu, Wei; Ji, Xiaoli; Xia, Yankai; Hu, Lingqing; Chen, Daozhen; Wang, Xinru

    2016-01-01

    Gold nanorods (GNRs) are among the most commonly used nanomaterials. However, thus far, little is known about their harmful effects on male reproduction. Studies from our laboratory have demonstrated that GNRs could decrease glycine synthesis, membrane permeability, mitochondrial membrane potential and disrupt blood-testis barrier factors in TM-4 Sertoli cells. Imprinted genes play important roles in male reproduction and have been identified as susceptible loci to environmental insults by chemicals because they are functionally haploid. In this original study, we investigated the extent to which imprinted genes become deregulated in TM-4 Sertoli cells when treated with low dose of GNRs. The expression levels of 44 imprinted genes were analyzed by quantitative real-time PCR in TM-4 Sertoli cells after a low dose of (10 nM) GNRs treatment for 24 h. We found significantly diminished expression of Kcnq1, Ntm, Peg10, Slc22a2, Pwcr1, Gtl2, Nap1l5, Peg3 and Slc22a2, while Plagl1 was significantly overexpressed. Additionally, four (Kcnq1, Slc22a18, Pwcr1 and Peg3) of 10 abnormally expressed imprinted genes were found to be located on chromosome 7. However, no significant difference of imprinted miRNA genes was observed between the GNRs treated group and controls. Our study suggested that aberrant expression of imprinted genes might be an underlying mechanism for the GNRs-induced reproductive toxicity in TM-4 Sertoli cells. PMID:26938548

  3. Placental expression of imprinted genes varies with sampling site and mode of delivery

    PubMed Central

    Janssen, A.B.; Tunster, S.J.; Savory, N.; Holmes, A.; Beasley, J.; Parveen, S.A.R.; Penketh, R.J.A.; John, R.M.

    2015-01-01

    Imprinted genes, which are monoallelically expressed by virtue of an epigenetic process initiated in the germline, are known to play key roles in regulating fetal growth and placental development. Numerous studies are investigating the expression of these imprinted genes in the human placenta in relation to common complications of pregnancy such as fetal growth restriction and preeclampsia. This study aimed to determine whether placental sampling protocols or other factors such as fetal sex, gestational age and mode of delivery may influence the expression of imprinted genes predicted to regulate placental signalling. Methods Term placentas were collected from Caucasian women delivering at University Hospital of Wales or Royal Gwent Hospital within two hours of delivery. Expression of the imprinted genes PHLDA2, CDKN1C, PEG3 and PEG10 was assayed by quantitative real time PCR. Intraplacental gene expression was analysed (N = 5). Placental gene expression was compared between male (N = 11) and female (N = 11) infants, early term (N = 8) and late term (N = 10) deliveries and between labouring (N = 13) and non-labouring (N = 21) participants. Results The paternally expressed imprinted genes PEG3 and PEG10 were resilient to differences in sampling site, fetal sex, term gestational age and mode of delivery. The maternally expressed imprinted gene CDKN1C was elevated over 2-fold (p < 0.001) in placenta from labouring deliveries compared with elective caesarean sections. In addition, the maternally expressed imprinted gene PHLDA2 was elevated by 1.8 fold (p = 0.01) in samples taken at the distal edge of the placenta compared to the cord insertion site. Conclusion These findings support the reinterpretation of existing data sets on these genes in relation to complications of pregnancy and further reinforce the importance of optimising and unifying placental collection protocols for future studies. PMID:26162698

  4. Identification of imprinted genes using a novel screening method based on asynchronous DNA replication

    SciTech Connect

    Kawame, H.; Hansen, R.S.; Gartler, S.M.

    1994-09-01

    Genomic imprinting refers to the process of epigenetic change that occurs during germ cell development that results in either maternal- or paternal-specific gene expression. Identification of imprinted genes is of primary importance to the understanding of imprinting mechanisms and the role of specific imprinted genes in human disease. Recently, it has been established that chromosomal regions known to contain imprinted genes replicate asynchronously. We propose a novel screening method to identify imprinted genes based on replication asynchrony as a marker for imprinted domains. Dividing human cells were pulse-labeled with BrdU and separated into different fractions of S-phase by flow cytometry. A library of late-replicating inter-Alu sequences should be enriched in gene-associated sequences that replicate early on one chromosome and late on the other homologue. Clones were analyzed for replication timing by hybridization to inter-Alu replication profiles. Candidates for replication asynchrony exhibited broad or biphasic replication timing, and these were analyzed for chromosomal location by hybridizations to inter-Alu products from a hybrid mapping panel. Initial screening of 123 clones resulted in 3 asynchronously-replicating clones that localized to single chromosomes. Chromosome 17 and chromosome 19 candidates might be located in regions thought to be imprinted by synteny with mouse chromosomes. A chromosome 15 clone was further characterized because of its possible localization to the Prader-Willi/Angelman locus. This sequence was localized outside the region deleted in Prader-Willi patients, and was found to be expressed in human cell lines. Replication asynchrony for this sequence appears to be polymorphic because cells derived from some individuals indicated synchronous replication. This appears to be the first example of a polymorphism in replication asynchrony.

  5. Analysis of Imprinted Gene Expression in Normal Fertilized and Uniparental Preimplantation Porcine Embryos

    PubMed Central

    Park, Chi-Hun; Uh, Kyung-Jun; Mulligan, Brendan P.; Jeung, Eui-Bae; Hyun, Sang-Hwan; Shin, Taeyoung; Ka, Hakhyun; Lee, Chang-Kyu

    2011-01-01

    In the present study quantitative real-time PCR was used to determine the expression status of eight imprinted genes (GRB10, H19, IGF2R, XIST, IGF2, NNAT, PEG1 and PEG10) during preimplantation development, in normal fertilized and uniparental porcine embryos. The results demonstrated that, in all observed embryo samples, a non imprinted gene expression pattern up to the 16-cell stage of development was common for most genes. This was true for all classes of embryo, regardless of parental-origins and the direction of imprint. However, several differentially expressed genes (H19, IGF2, XIST and PEG10) were detected amongst the classes at the blastocyst stage of development. Most interestingly and despite the fact that maternally and paternally expressed genes should not be expressed in androgenones and parthenogenones, respectively, both uniparental embryos expressed these genes when tested for in this study. In order to account for this phenomenon, we compared the expression patterns of eight imprinted genes along with the methylation status of the IGF2/H19 DMR3 in haploid and diploid parthenogenetic embryos. Our findings revealed that IGF2, NNAT and PEG10 were silenced in haploid but not diploid parthenogenetic blastocysts and differential methylation of the IGF2/H19 DMR3 was consistently observed between haploid and diploid parthenogenetic blastocysts. These results appear to suggest that there exists a process to adjust the expression status of imprinted genes in diploid parthenogenetic embryos and that this phenomenon may be associated with altered methylation at an imprinting control region. In addition we believe that imprinted expression occurs in at least four genes, namely H19, IGF2, XIST and PEG10 in porcine blastocyst stage embryos. PMID:21804912

  6. An open-pollinated design for mapping imprinting genes in natural populations.

    PubMed

    Sun, Lidan; Zhu, Xuli; Bo, Wenhao; Xu, Fang; Cheng, Tangren; Zhang, Qixiang; Wu, Rongling

    2015-05-01

    With the increasing recognition of its role in trait and disease development, it is crucial to account for genetic imprinting to illustrate the genetic architecture of complex traits. Genetic mapping can be innovated to test and estimate effects of genetic imprinting in a segregating population derived from experimental crosses. Here, we describe and assess a design for imprinting detection in natural plant populations. This design is to sample maternal plants at random from a natural population and collect open-pollinated (OP) seeds randomly from each maternal plant and germinate them into seedlings. A two-stage hierarchical platform is constructed to jointly analyze maternal and OP progeny markers. Through tracing the segregation and transmission of alleles from the parental to progeny generation, this platform allows parent-of-origin-dependent gene expression to be discerned, providing an avenue to estimate the effect of imprinting genes on a quantitative trait. The design is derived to estimate imprinting effects expressed at the haplotype level. Its usefulness and utilization were validated through computer simulation. This OP-based design provides a tool to detect the genomic distribution and pattern of imprinting genes as an important component of heritable variation that is neglected in traditional genetic studies of complex traits. PMID:24927940

  7. Discovery of a novel imprinted gene by transcriptional analysis of parthenogenetic embryonic stem cells

    PubMed Central

    Sritanaudomchai, Hathaitip; Ma, Hong; Clepper, Lisa; Gokhale, Sumita; Bogan, Randy; Hennebold, Jon; Wolf, Don; Mitalipov, Shoukhrat

    2010-01-01

    BACKGROUND Parthenogenetic embryonic stem cells (PESCs) may have future utilities in cell replacement therapies since they are closely related to the female from which the activated oocyte was obtained. Furthermore, the avoidance of parthenogenetic development in mammals provides the most compelling rationale for the evolution of genomic imprinting, and the biological process of parthenogenesis raises complex issues regarding differential gene expression. METHODS AND RESULTS We describe here homozygous rhesus monkey PESCs derived from a spontaneously duplicated, haploid oocyte genome. Since the effect of homozygosity on PESCs pluripotency and differentiation potential is unknown, we assessed the similarities and differences in pluripotency markers and developmental potential by in vitro and in vivo differentiation of homozygous and heterozygous PESCs. To understand the differences in gene expression regulation between parthenogenetic and biparental embryonic stem cells (ESCs), we conducted microarray analysis of genome-wide mRNA profiles of primate PESCs and ESCs derived from fertilized embryos using the Affymetrix Rhesus Macaque Genome array. Several known paternally imprinted genes were in the highly down-regulated group in PESCs compared with ESCs. Furthermore, allele-specific expression analysis of other genes whose expression is also down-regulated in PESCs, led to the identification of one novel imprinted gene, inositol polyphosphate-5-phosphatase F (INPP5F), which was exclusively expressed from a paternal allele. CONCLUSION Our findings suggest that PESCs could be used as a model for studying genomic imprinting, and in the discovery of novel imprinted genes. PMID:20522441

  8. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster.

    PubMed

    Rosenfeld, Jill A; Fox, Joyce E; Descartes, Maria; Brewer, Fallon; Stroud, Tracy; Gorski, Jerome L; Upton, Sheila J; Moeschler, John B; Monteleone, Berrin; Neill, Nicholas J; Lamb, Allen N; Ballif, Blake C; Shaffer, Lisa G; Ravnan, J Britt

    2015-02-01

    Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes. PMID:25756153

  9. Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain.

    PubMed

    Kim, J; Bergmann, A; Wehri, E; Lu, X; Stubbs, L

    2001-09-01

    We have isolated Kruppel-type (C2H2) zinc-finger genes, ZIM3 (zinc-finger gene 3 from imprinted domain) and ZNF264, located downstream of human and mouse USP29 genes (encoding ubiquitin-specific processing protease 29). In human, both ZIM3 and ZNF264 encode zinc-finger proteins with Kruppel-associated box (KRAB) A and B domains at the amino-terminal regions of the predicted proteins. In contrast, mouse Zim3 and Zfp264 seem to have lost protein-coding capability based on the lack of open reading frames (ORFs) in their cDNA sequences. In particular, the 3' end of the Zim3 transcript overlaps with the coding region of the adjacent gene Usp29 in an antisense orientation, indicating the conversion of mouse Zim3 into an antisense transcript gene for Usp29. The expression patterns of ZIM3 and ZNF264 have been largely conserved between human and mouse, with testis-specific expression of ZIM3 and ubiquitous expression of ZNF264, but high expression levels in adult testes in both species. Our studies also demonstrate that both mouse genes are imprinted with maternal expression of Zim3 in adult testes and paternal expression of Zfp264 in neonatal and adult brain. The reciprocal imprinting of two neighboring mouse genes, Zim3 and Zfp264, is consistent with a pattern observed frequently in other imprinted domains, and suggests that the imprinting of these two genes might be coregulated. PMID:11543637

  10. Methods for detecting interactions between imprinted genes and environmental exposures using birth cohort designs with mother-offspring pairs.

    PubMed

    Wang, Shuang; Yu, Zhaoxia; Miller, Rachel L; Tang, Deliang; Perera, Frederica P

    2011-01-01

    Genomic imprinting is a form of epigenetic regulation in mammals in which the same allele of a gene is expressed differently depending on the parental origin of the allele. Traditionally, the detection of imprinted genes that affect complex diseases has been focused on linkage designs with pedigrees or case-parent designs with case-parent trios. In the past two decades, the birth cohort design with mother-offspring pairs has been applied to understand better the effect of environmental influences during pregnancy and beginning of life on the growth and development of children. No work has been done on the detection of imprinted genes using birth cohort designs. Moreover, although the importance of imprinting has been well recognized, no study has looked at how environmental exposures modify the effects of imprinted genes. In this study, we show that the proposed imprinting test using the birth cohort design with mother-offspring pairs is an efficient test for testing the interactions between imprinted genes and environmental exposures. Through extensive simulation studies and a real data application, the proposed imprinting test has demonstrated much improved power in detecting gene-environment interactions than that of a test assuming the Mendelian dominant model when the true underlying genetic model is imprinting. PMID:21778739

  11. Paternally expressed imprinted genes establish postzygotic hybridization barriers in Arabidopsis thaliana

    PubMed Central

    Wolff, Philip; Jiang, Hua; Wang, Guifeng; Santos-González, Juan; Köhler, Claudia

    2015-01-01

    Genomic imprinting is an epigenetic phenomenon causing parent-of-origin specific differential expression of maternally and paternally inherited alleles. While many imprinted genes have been identified in plants, the functional roles of most of them are unknown. In this study, we systematically examine the functional requirement of paternally expressed imprinted genes (PEGs) during seed development in Arabidopsis thaliana. While none of the 15 analyzed peg mutants has qualitative or quantitative abnormalities of seed development, we identify three PEGs that establish postzygotic hybridization barriers in the endosperm, revealing that PEGs have a major role as speciation genes in plants. Our work reveals that a subset of PEGs maintains functional roles in the inbreeding plant Arabidopsis that become evident upon deregulated expression. DOI: http://dx.doi.org/10.7554/eLife.10074.001 PMID:26344545

  12. Paternally expressed imprinted genes establish postzygotic hybridization barriers in Arabidopsis thaliana.

    PubMed

    Wolff, Philip; Jiang, Hua; Wang, Guifeng; Santos-González, Juan; Köhler, Claudia

    2015-01-01

    Genomic imprinting is an epigenetic phenomenon causing parent-of-origin specific differential expression of maternally and paternally inherited alleles. While many imprinted genes have been identified in plants, the functional roles of most of them are unknown. In this study, we systematically examine the functional requirement of paternally expressed imprinted genes (PEGs) during seed development in Arabidopsis thaliana. While none of the 15 analyzed peg mutants has qualitative or quantitative abnormalities of seed development, we identify three PEGs that establish postzygotic hybridization barriers in the endosperm, revealing that PEGs have a major role as speciation genes in plants. Our work reveals that a subset of PEGs maintains functional roles in the inbreeding plant Arabidopsis that become evident upon deregulated expression. PMID:26344545

  13. Maintenance of Paternal Methylation and Repression of the Imprinted H19 Gene Requires MBD3

    PubMed Central

    Reese, Kimberly J; Lin, Shu; Verona, Raluca I; Schultz, Richard M; Bartolomei, Marisa S

    2007-01-01

    Paternal repression of the imprinted H19 gene is mediated by a differentially methylated domain (DMD) that is essential to imprinting of both H19 and the linked and oppositely imprinted Igf2 gene. The mechanisms by which paternal-specific methylation of the DMD survive the period of genome-wide demethylation in the early embryo and are subsequently used to govern imprinted expression are not known. Methyl-CpG binding (MBD) proteins are likely candidates to explain how these DMDs are recognized to silence the locus, because they preferentially bind methylated DNA and recruit repression complexes with histone deacetylase activity. MBD RNA and protein are found in preimplantation embryos, and chromatin immunoprecipitation shows that MBD3 is bound to the H19 DMD. To test a role for MBDs in imprinting, two independent RNAi-based strategies were used to deplete MBD3 in early mouse embryos, with the same results. In RNAi-treated blastocysts, paternal H19 expression was activated, supporting the hypothesis that MBD3, which is also a member of the Mi-2/NuRD complex, is required to repress the paternal H19 allele. RNAi-treated blastocysts also have reduced levels of the Mi-2/NuRD complex protein MTA-2, which suggests a role for the Mi-2/NuRD repressive complex in paternal-specific silencing at the H19 locus. Furthermore, DNA methylation was reduced at the H19 DMD when MBD3 protein was depleted. In contrast, expression and DNA methylation were not disrupted in preimplantation embryos for other imprinted genes. These results demonstrate new roles for MBD3 in maintaining imprinting control region DNA methylation and silencing the paternal H19 allele. Finally, MBD3-depleted preimplantation embryos have reduced cell numbers, suggesting a role for MBD3 in cell division. PMID:17708683

  14. Genomic Imprinting

    PubMed Central

    Bajrami, Emirjeta; Spiroski, Mirko

    2016-01-01

    BACKGROUND: Genomic imprinting is the inheritance out of Mendelian borders. Many of inherited diseases and human development violates Mendelian law of inheritance, this way of inheriting is studied by epigenetics. AIM: The aim of this review is to analyze current opinions and options regarding to this way of inheriting. RESULTS: Epigenetics shows that gene expression undergoes changes more complex than modifications in the DNA sequence; it includes the environmental influence on the gametes before conception. Humans inherit two alleles from mother and father, both are functional for the majority of the genes, but sometimes one is turned off or “stamped” and doesn’t show in offspring, that gene is imprinted. Imprinting means that that gene is silenced, and gene from other parent is expressed. The mechanisms for imprinting are still incompletely defined, but they involve epigenetic modifications that are erased and then reset during the creation of eggs and sperm. Genomic imprinting is a process of silencing genes through DNA methylation. The repressed allele is methylated, while the active allele is unmethylated. The most well-known conditions include Prader-Willi syndrome, and Angelman syndrome. Both of these syndromes can be caused by imprinting or other errors involving genes on the long arm of chromosome 15. CONCLUSIONS: Genomic imprinting and other epigenetic mechanisms such as environment is shown that plays role in offspring neurodevelopment and autism spectrum disorder. PMID:27275355

  15. A First-Stage Approximation to Identify New Imprinted Genes through Sequence Analysis of Its Coding Regions

    PubMed Central

    Daura-Oller, Elias; Cabré, Maria; Montero, Miguel A.; Paternáin, José L.; Romeu, Antoni

    2009-01-01

    In the present study, a positive training set of 30 known human imprinted gene coding regions are compared with a set of 72 randomly sampled human nonimprinted gene coding regions (negative training set) to identify genomic features common to human imprinted genes. The most important feature of the present work is its ability to use multivariate analysis to look at variation, at coding region DNA level, among imprinted and non-imprinted genes. There is a force affecting genomic parameters that appears through the use of the appropriate multivariate methods (principle components analysis (PCA) and quadratic discriminant analysis (QDA)) to analyse quantitative genomic data. We show that variables, such as CG content, [bp]% CpG islands, [bp]% Large Tandem Repeats, and [bp]% Simple Repeats, are able to distinguish coding regions of human imprinted genes. PMID:19360135

  16. Early embryonic failure: Expression and imprinted status of candidate genes on human chromosome 21

    SciTech Connect

    Sherman, L.S.; Bennett, P.R.; Moore, G.E.

    1994-09-01

    Two cases of maternal uniparental (hetero)disomy for human chromosome 21 (mUPD21) have been identified in a systematic search for UPD in 23 cases of early embryonic failure (EEF). Bi-parental origin of the other chromosome pairs was confirmed using specific VNTR probes or dinucleotide repeat analysis. Both maternally and paternally derived isochromosomes 21q have previously been identified in two individuals with normal phenotypes. Full UPD21 has a different mechanism of origin than uniparental isochromosome 21q and its effect on imprinted genes and phenotypic outcome will therefore not necessarily be the same. EEF associated with mUPD21 suggests that developmentally important genes on HSA 21 may be imprinted such that they are only expressed from either the maternally or paternally derived alleles. We have searched for monoallelic expression of candidate genes on HSA 21 in human pregnancy (CBS, IFNAR, COL6A1) using intragenic DNA polymorphisms. These genes were chosen either because their murine homologues lie in imprinted regions or because they are potentially important in embryogenesis. Once imprinted candidate genes have been identified, their methylation status and expression in normal, early embryonic failure and uniparental disomy 21 pregnancies will be studied. At the same time, a larger number of cases of EEF are being examined to further investigate the incidence of UPD21 in this group.

  17. Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1) in development: implications for the evolution of imprinting.

    PubMed

    da Rocha, Simao Teixeira; Charalambous, Marika; Lin, Shau-Ping; Gutteridge, Isabel; Ito, Yoko; Gray, Dionne; Dean, Wendy; Ferguson-Smith, Anne C

    2009-02-01

    Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantage conferred by imprinting is not understood but is hypothesised to act on dosage-critical genes. Here, we report a unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1, normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosage and survival that fixes an upper limit on growth promotion by Dlk1, and we hypothesize that trade-off between growth and lethality might have driven imprinting at this locus. PMID:19247431

  18. Gene Dosage Effects of the Imprinted Delta-Like Homologue 1 (Dlk1/Pref1) in Development: Implications for the Evolution of Imprinting

    PubMed Central

    Teixeira da Rocha, Simao; Charalambous, Marika; Lin, Shau-Ping; Gutteridge, Isabel; Ito, Yoko; Gray, Dionne; Dean, Wendy; Ferguson-Smith, Anne C.

    2009-01-01

    Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantage conferred by imprinting is not understood but is hypothesised to act on dosage-critical genes. Here, we report a unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1, normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosage and survival that fixes an upper limit on growth promotion by Dlk1, and we hypothesize that trade-off between growth and lethality might have driven imprinting at this locus. PMID:19247431

  19. Genome-wide screen of genes imprinted in sorghum endosperm, and the roles of allelic differential cytosine methylation.

    PubMed

    Zhang, Meishan; Li, Ning; He, Wenan; Zhang, Huakun; Yang, Wei; Liu, Bao

    2016-02-01

    Imprinting is an epigenetic phenomenon referring to allele-biased expression of certain genes depending on their parent of origin. Accumulated evidence suggests that, while imprinting is a conserved mechanism across kingdoms, the identities of the imprinted genes are largely species-specific. Using deep RNA sequencing of endosperm 14 days after pollination in sorghum, 5683 genes (29.27% of the total 19 418 expressed genes) were found to harbor diagnostic single nucleotide polymorphisms between two parental lines. The analysis of parent-of-origin expression patterns in the endosperm of a pair of reciprocal F1 hybrids between the two sorghum lines led to identification of 101 genes with ≥ fivefold allelic expression difference in both hybrids, including 85 maternal expressed genes (MEGs) and 16 paternal expressed genes (PEGs). Thirty of these genes were previously identified as imprinted in endosperm of maize (Zea mays), rice (Oryza sativa) or Arabidopsis, while the remaining 71 genes are sorghum-specific imprinted genes relative to these three plant species. Allele-biased expression of virtually all of the 14 tested imprinted genes (nine MEGs and five PEGs) was validated by pyrosequencing using independent sources of RNA from various developmental stages and dissected parts of endosperm. Forty-six imprinted genes (30 MEGs and 16 PEGs) were assayed by quantitative RT-PCR, and the majority of them showed endosperm-specific or preferential expression relative to embryo and other tissues. DNA methylation analysis of the 5' upstream region and gene body for seven imprinted genes indicated that, while three of the four PEGs were associated with hypomethylation of maternal alleles, no MEG was associated with allele-differential methylation. PMID:26718755

  20. The role and interaction of imprinted genes in human fetal growth

    PubMed Central

    Moore, Gudrun E.; Ishida, Miho; Demetriou, Charalambos; Al-Olabi, Lara; Leon, Lydia J.; Thomas, Anna C.; Abu-Amero, Sayeda; Frost, Jennifer M.; Stafford, Jaime L.; Chaoqun, Yao; Duncan, Andrew J.; Baigel, Rachel; Brimioulle, Marina; Iglesias-Platas, Isabel; Apostolidou, Sophia; Aggarwal, Reena; Whittaker, John C.; Syngelaki, Argyro; Nicolaides, Kypros H.; Regan, Lesley; Monk, David; Stanier, Philip

    2015-01-01

    Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown–rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (−132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses

  1. Effects of endocrine disruptors on imprinted gene expression in the mouse embryo

    PubMed Central

    Tran, Diana A; Rivas, Guillermo E; Singh, Purnima; Pfeifer, Gerd P

    2011-01-01

    Environmental endocrine disruptors (EDs) are synthetic chemicals that resemble natural hormones and are known to cause epigenetic perturbations. EDs have profound effects on development and fertility. Imprinted genes had been identified as candidate susceptibility loci to environmental insults because they are functionally haploid, and because the imprints undergo epigenetic resetting between generations. To screen for possible epigenetic perturbations caused by EDs at imprinted loci, we treated pregnant mice daily between 8.5 and 12.5 days post coitum (dpc) with di-(2-ethylhexyl)-phthalate (DEHP), bisphenol A (BPA), vinclozolin (VZ) or control oil vehicle. After isolating RNA from the placenta, yolk sac, amnion, head, body, heart, liver, lung, stomach and intestines of 13.5 dpc embryos we measured the allele-specific expression of 39 imprinted transcripts using multiplex single nucleotide primer extension (SNuPE) assays. In this representative data set we identified only a small number of transcripts that exhibited a substantial relaxation of imprinted expression with statistical significance: Slc22a18 with 10% relaxation in the embryo after BPA treatment; Rtl1as with 11 and 16% relaxation in the lung and placenta, respectively after BPA treatment; and Rtl1 with 12% relaxation in the yolk sac after DEHP treatment. Additionally, the standard deviation of allele-specificity increased in various organs after ED treatment for several transcripts including Igf2r, Rasgrf1, Usp29, Slc38a4 and Xist. Our data suggest that the maintenance of strongly biased monoallelic expression of imprinted genes is generally insensitive to EDs in the 13.5 dpc embryo and extra-embryonic organs, but is not immune to those effects. PMID:21636974

  2. Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs.

    PubMed

    Ma, Jing; Chen, Xi; Liu, Yanan; Xie, Qunhui; Sun, Yawen; Chen, Jingshan; Leng, Ling; Yan, Huan; Zhao, Bin; Tang, Naijun

    2015-12-01

    Ancestral TCDD exposure could induce epigenetic transgenerational phenotypes, which may be mediated in part by imprinted gene inheritance. The aim of our study was to evaluate the transgenerational effects of ancestral TCDD exposure on the imprinted gene insulin-like growth factor-2 (Igf2) in rat somatic tissue. TCDD was administered daily by oral gavage to groups of F0 pregnant SD rats at dose levels of 0 (control), 200 or 800 ng/kg bw during gestation day 8-14. Animal transgenerational model of ancestral exposure to TCDD was carefully built, avoiding sibling inbreeding. Hepatic Igf2 expression of the TCDD male progeny was decreased concomitantly with hepatic damage and increased activities of serum hepatic enzymes both in the F1 and F3 generation. Imprinted Control Region (ICR) of Igf2 manifested a hypermethylated pattern, whereas methylation status in the Differentially Methylated Region 2 (DMR2) showed a hypomethylated manner in the F1 generation. These epigenetic alterations in these two regions maintained similar trends in the F3 generation. Meanwhile, the expressions of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) changed in a non-monotonic manner both in the F1 and F3 generation. This study provides evidence that ancestral TCDD exposure may promote epigenetic transgenerational alterations of imprinted gene Igf2 in adult somatic tissue. PMID:26455773

  3. Beckwith-Wiedemann syndrome and imprinted genes on chromosome 11p15.5

    SciTech Connect

    Weksberg, R.; Perlikowski, S.; Squire, J.

    1994-09-01

    Beckwith-Wiedemann syndrome (BWS) is a syndrome characterized by generalized and regional overgrowth as well as a predisposition to specific embryonal tumors. We have previously reported biallelic expression of insulin like growth factor 2 (IGF2) in fibroblasts from sporadic cases of BWS. In these cells, the normal expression pattern for IGF2 is allele-specific and derived from the paternal allele. To determine whether biallelic expression of IGF2 in BWS patients results from aberrant regulation of a single gene or multiple genes in an imprinted domain, we undertook the study of a second gene in the 11p15.5 imprinted region. H19 is normally stringently regulated, expressed primarily from the maternal allele, and in many tissues reciprocal expression of H19 and IGF2 has been documented. Since no protein product for H19 has been identified, the RNA itself may be biologically active and it may have a tumor suppressor function. Moreover, H19 has been suggested as a candidate gene in BWS, especially in autosomal dominant pedigrees. Using an Rsa1 polymorphism in the transcribed region of H19, we found that the expression of H19 in 8 patients with sporadic BWS is consistently nonallelic and in the informative cases is always from the maternal allele. This is also true for the two cases of BWS where biallelic IGF2 expression has been documented. We conclude that IGF2 biallelic expression does not represent a general loss of imprint control. If H19 and IGF2 do normally respond to common signals within an imprinted domain at 11p15.5, we suggest that BWS patients with biallelic IGF2 expression can escape from such imprinting constraints. To study this region in more detail, we have developed a replication timing assay for IGF2 and H19 to determine whether loss of asynchronous replication accompanies biallelic IGF2 expression.

  4. Characterization of the IGF2 Imprinted Gene Methylation Status in Bovine Oocytes during Folliculogenesis

    PubMed Central

    Mendonça, Anelise dos Santos; Guimarães, Ana Luíza Silva; da Silva, Naiara Milagres Augusto; Caetano, Alexandre Rodrigues; Dode, Margot Alves Nunes; Franco, Maurício Machaim

    2015-01-01

    DNA methylation reprogramming occurs during mammalian gametogenesis and embryogenesis. Sex-specific DNA methylation patterns at specific CpG islands controlling imprinted genes are acquired during this window of development. Characterization of the DNA methylation dynamics of imprinted genes acquired by oocytes during folliculogenesis is essential for understanding the physiological and genetic aspects of female gametogenesis and to determine the parameters for oocyte competence. This knowledge can be used to improve in vitro embryo production (IVP), specifically because oocyte competence is one of the most important aspects determining the success of IVP. Imprinted genes, such as IGF2, play important roles in embryo development, placentation and fetal growth. The aim of this study was to characterize the DNA methylation profile of the CpG island located in IGF2 exon 10 in oocytes during bovine folliculogenesis. The methylation percentages in oocytes from primordial follicles, final secondary follicles, small antral follicles, large antral follicles, MII oocytes and spermatozoa were 73.74 ± 2.88%, 58.70 ± 7.46%, 56.00 ± 5.58%, 65.77 ± 5.10%, 56.35 ± 7.45% and 96.04 ± 0.78%, respectively. Oocytes from primordial follicles showed fewer hypomethylated alleles (15.5%) than MII oocytes (34.6%) (p = 0.039); spermatozoa showed only hypermethylated alleles. Moreover, MII oocytes were less methylated than spermatozoa (p<0.001). Our results showed that the methylation pattern of this region behaves differently between mature oocytes and spermatozoa. However, while this region has a classical imprinted pattern in spermatozoa that is fully methylated, it was variable in mature oocytes, showing hypermethylated and hypomethylated alleles. Furthermore, our results suggest that this CpG island may have received precocious reprogramming, considering that the hypermethylated pattern was already found in growing oocytes from primordial follicles. These results may contribute to

  5. Imprinted survival genes preclude loss of heterozygosity of chromosome 7 in cancer cells.

    PubMed

    Boot, Arnoud; Oosting, Jan; de Miranda, Noel Fcc; Zhang, Yinghui; Corver, Willem E; van de Water, Bob; Morreau, Hans; van Wezel, Tom

    2016-09-01

    The genomes of a wide range of cancers, including colon, breast, and thyroid cancers, frequently show copy number gains of chromosome 7 and rarely show loss of heterozygosity. The molecular basis for this phenomenon is unknown. Strikingly, oncocytic follicular thyroid carcinomas can display an extreme genomic profile, with homozygosity of all chromosomes except for chromosome 7. The observation that homozygosity of chromosome 7 is never observed suggests that retention of heterozygosity is essential for cells. We hypothesized that cell survival genes are genetically imprinted on either of two copies of chromosome 7, which thwarts loss of heterozygosity at this chromosome in cancer cells. By employing a DNA methylation screen and gene expression analysis, we identified six imprinted genes that force retention of heterozygosity on chromosome 7. Subsequent knockdown of gene expression showed that CALCR, COPG2, GRB10, KLF14, MEST, and PEG10 were essential for cancer cell survival, resulting in reduced cell proliferation, G1 -phase arrest, and increased apoptosis. We propose that imprinted cell survival genes provide a genetic basis for retention of chromosome 7 heterozygosity in cancer cells. The monoallelically expressed cell survival genes identified in this study, and the cellular pathways that they are involved in, offer new therapeutic targets for the treatment of tumours showing retention of heterozygosity on chromosome 7. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27265324

  6. Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma

    SciTech Connect

    Kato, Mitsuo V.; Nagayoshi, Mariko; Shimuzu, Takashi

    1996-11-01

    Epidemiological and genetic studies of retinoblastoma (RB) suggested that imprinted genes might be genetically linked to the RB gene. In this study, we found that the human serotonin-receptor, HTR2, gene, which had been mapped nearby the RB gene on chromosome 13, was expressed only in human fibroblasts with a maternal allele and not in cells without a maternal allele. The 5{prime} genomic region of the human HTR2 gene was cloned by PCR-mediated method. Only the 5{prime} region of the gene was methylated in cells with the maternal gene, and it was not methylated in cells without the maternal gene. A polymorphism of PvuII site of the gene was also found and useful for the segregation analysis in a family of an RB patient and for analysis of loss of heterozygosity on chromosome 13 in tumor and its parental origin. These results suggest that the human HTR2 gene might be affected by genomic imprinting and that exclusive expression of the maternal HTR2 gene may be associated with the delayed occurrence of RB, which had lost the maternal chromosome 13. 33 refs., 5 figs., 2 tabs.

  7. Monoallelic Loss of the Imprinted Gene Grb10 Promotes Tumor Formation in Irradiated Nf1+/- Mice

    PubMed Central

    Mroue, Rana; Huang, Brian; Braunstein, Steve; Firestone, Ari J.; Nakamura, Jean L.

    2015-01-01

    Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis. PMID:26000738

  8. Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit.

    PubMed

    Pun, F W; Zhao, C; Lo, W-S; Ng, S-K; Tsang, S-Y; Nimgaonkar, V; Chung, W S; Ungvari, G S; Xue, H

    2011-05-01

    Schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2 or rs2290732 (G/A) in the neighboring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the disease-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could have an impact on the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia. PMID:20404824

  9. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene

    SciTech Connect

    Glenn, C.C.; Jong, T.C.; Filbrandt, M.M.

    1996-02-01

    The human SNRPN (small nuclear ribonucleoprotein polypeptide N) gene is one of a gene family that encode proteins involved in pre-mRNA splicing and maps to the smallest deletion region involved in the Prader-Willi syndrome (PWS) within chromosome 15q11-q13. Paternal only expression of SNRPN has previously been demonstrated by use of cell lines from PWS patients (maternal allele only) and Angelman syndrome (AS) patients (paternal allele only). We have characterized two previously unidentified 5{prime} exons of the SNRPN gene and demonstrate that exons -1 and 0 are included in the full-length transcript. This gene is expressed in a wide range of somatic tissues and at high, approximately equal levels in all regions of the brain. Both the first exon of SNRPN (exon -1) and the putative transcription start site are embedded within a CpG island. This CpG island is extensively methylated on the repressed maternal allele and is unmethylated on the expressed paternal allele, in a wide range of fetal and adult somatic cells. This provides a quick and highly reliable diagnostic assay for PWS and AS, which is based on DNA-methylation analysis that has been tested on >100 patients in a variety of tissues. Conversely, several CpG sites {approximately}22 kb downstream of the transcription start site in intron 5 are preferentially methylated on the expressed paternal allele in somatic tissues and male germ cells, whereas these same sites are unmethylated in fetal oocytes. These findings are consistent with a key role for DNA methylation in the imprinted inheritance and subsequent gene expression of the human SNRPN gene. 59 refs., 9 figs., 1 tab.

  10. Heat-Induced Release of Epigenetic Silencing Reveals the Concealed Role of an Imprinted Plant Gene

    PubMed Central

    Sanchez, Diego H.; Paszkowski, Jerzy

    2014-01-01

    Epigenetic mechanisms suppress the transcription of transposons and DNA repeats; however, this suppression can be transiently released under prolonged heat stress. Here we show that the Arabidopsis thaliana imprinted gene SDC, which is silent during vegetative growth due to DNA methylation, is activated by heat and contributes to recovery from stress. SDC activation seems to involve epigenetic mechanisms but not canonical heat-shock perception and signaling. The heat-mediated transcriptional induction of SDC occurs particularly in young developing leaves and is proportional to the level of stress. However, this occurs only above a certain window of absolute temperatures and, thus, resembles a thermal-sensing mechanism. In addition, the re-silencing kinetics during recovery can be entrained by repeated heat stress cycles, suggesting that epigenetic regulation in plants may conserve memory of stress experience. We further demonstrate that SDC contributes to the recovery of plant biomass after stress. We propose that transcriptional gene silencing, known to be involved in gene imprinting, is also co-opted in the specific tuning of SDC expression upon heat stress and subsequent recovery. It is therefore possible that dynamic properties of the epigenetic landscape associated with silenced or imprinted genes may contribute to regulation of their expression in response to environmental challenges. PMID:25411840

  11. Imprinting analysis of porcine MAGEL2 gene in two fetal stages and association analysis with carcass traits.

    PubMed

    Guo, Ling; Qiao, Mu; Wang, Chao; Zheng, Rong; Xiong, Yuan-Zhu; Deng, Chang-Yan

    2012-01-01

    Imprinted genes play an essential role in the regulation of fetal growth, development and function of the placenta, however only a limited number of imprinted genes have been studied in swine. In this study, we cloned and characterized porcine MAGEL2 (melanoma antigen-like gene 2), and also identified its imprinting status during porcine fetal development. The complete open reading frame (ORF) encoding 1,193 amino acids was isolated and two single nucleotide polymorphisms (SNPs) (g.2592A>C and g.3277T>C) in the coding region were identified. The reciprocal Yorkshire×Meishan F1 hybrid model and the RT-PCR/RFLP method were used to detect the imprinting status of porcine MAGEL2 gene at two developmental stages of day 30 and 65 of gestation. Imprinting analysis showed that porcine MAGEL2 was paternally expressed in day 65 fetal tissues, including heart, liver, spleen, lung, kidney, stomach, small intestine, skeletal muscle, brain and placenta. Interestingly, we observed an imprinting variance of MAGEL2 gene in 30 dpc fetuses produced by the cross of Yorkshire boar×Meishan sow, in which seven heterozygous fetuses were monoallelically expressed from the paternal allele but two were biallelically expressed from both the paternal and maternal alleles. Association analysis in a Yorkshire×Meishan F2 resource population showed that the mutation of g.2592A>C was significantly associated with dressed carcass percentage (P<0.05) and buttock fat thickness (P<0.05). Our results suggest that MAGEL2, as a novel imprinted gene in pig, might be a candidate gene affecting carcass traits and could provide important information for the functional study of imprinted genes during porcine development. PMID:21633897

  12. Dynamic expression of imprinted genes associates with maternally controlled nutrient allocation during maize endosperm development.

    PubMed

    Xin, Mingming; Yang, Ruolin; Li, Guosheng; Chen, Hao; Laurie, John; Ma, Chuang; Wang, Dongfang; Yao, Yingyin; Larkins, Brian A; Sun, Qixin; Yadegari, Ramin; Wang, Xiangfeng; Ni, Zhongfu

    2013-09-01

    In angiosperms, the endosperm provides nutrients for embryogenesis and seed germination and is the primary tissue where gene imprinting occurs. To identify the imprintome of early developing maize (Zea mays) endosperm, we performed high-throughput transcriptome sequencing of whole kernels at 0, 3, and 5 d after pollination (DAP) and endosperms at 7, 10, and 15 DAP, using B73 by Mo17 reciprocal crosses. We observed gradually increased expression of paternal transcripts in 3- and 5-DAP kernels. In 7-DAP endosperm, the majority of the genes tested reached a 2:1 maternal versus paternal ratio, suggesting that paternal genes are nearly fully activated by 7 DAP. A total of 116, 234, and 63 genes exhibiting parent-specific expression were identified at 7, 10, and 15 DAP, respectively. The largest proportion of paternally expressed genes was at 7 DAP, mainly due to the significantly deviated parental allele expression ratio of these genes at this stage, while nearly 80% of the maternally expressed genes (MEGs) were specific to 10 DAP and were primarily attributed to sharply increased expression levels compared with the other stages. Gene ontology enrichment analysis of the imprinted genes suggested that 10-DAP endosperm-specific MEGs are involved in nutrient uptake and allocation and the auxin signaling pathway, coincident with the onset of starch and storage protein accumulation. PMID:24058158

  13. Oppositely imprinted genes H19 and insulin-like growth factor 2 are coexpressed in human androgenetic trophoblast.

    PubMed Central

    Mutter, G L; Stewart, C L; Chaponot, M L; Pomponio, R J

    1993-01-01

    Human uniparental gestations such as gynogenetic ovarian teratomas and androgenetic complete hydatidiform moles provide a model to evaluate the integrity of parent-specific gene expression--i.e., imprinting--in the absence of a complementary parental genetic contribution. We studied expression, in these tissues, of the oppositely imprinted genes H19, which is an embryonic nontranslated RNA, and insulin-like growth factor type 2 (IGF2). Normal gestations only express H19 from the maternal allele and express IGF2 from the paternal allele, whereas neither is expressed from the maternal genome of gynogenetic gestations, and both are expressed from the paternal genome of androgenetic gestations. Coexpression of H19 and IGF2 in the androgenetic tissues was in a single population of cells, mononuclear trophoblast--the same cell type expressing these genes in biparental placentas. These results demonstrate that a biparental genome may be required for expression of the reciprocal IGF2/H19 imprint. Alternatively, biparental expression may be a normal feature of some imprinted genes in specific cell types. Additional experiments with other imprinted genes will clarify whether this reflects global failure of the imprinting process or a change specific to the IGF2/H19 locus. Images Figure 1 Figure 2 Figure 3 PMID:7692725

  14. The product of the imprinted H19 gene is an oncofetal RNA.

    PubMed Central

    Ariel, I.; Ayesh, S.; Perlman, E. J.; Pizov, G.; Tanos, V.; Schneider, T.; Erdmann, V. A.; Podeh, D.; Komitowski, D.; Quasem, A. S.; de Groot, N.; Hochberg, A.

    1997-01-01

    AIMS/BACKGROUND: The H19 gene is an imprinted, maternally expressed gene in humans. It is tightly linked and coregulated with the imprinted, paternally expressed gene of insulin-like growth factor 2. The H19 gene product is not translated into protein and functions as an RNA molecule. Although its role has been investigated for more than a decade, its biological function is still not understood fully. H19 is abundantly expressed in many tissues from early stages of embryogenesis through fetal life, and is down regulated postnatally. It is also expressed in certain childhood and adult tumours. This study was designed to screen the expression of H19 in human cancer and its relation to the expression of H19 in the fetus. METHODS: Using in situ hybridisation with a [35S] labelled probe, H19 mRNA was detected in paraffin wax sections of fetal tissues from the first and second trimesters of pregnancy and of a large array of human adult and childhood tumours arising from these tissues. RESULTS: The H19 gene is expressed in tumours arising from tissues which express this gene in fetal life. Its expression in the fetus and in cancer is closely linked with tissue differentiation. CONCLUSIONS: Based on these and previous data, H19 is neither a tumour suppressor gene nor an oncogene. Its product is an oncofetal RNA. The potential use of this RNA as a tumour marker should be evaluated. Images PMID:9208812

  15. Adult mouse brain gene expression patterns bear an embryologic imprint

    PubMed Central

    Zapala, Matthew A.; Hovatta, Iiris; Ellison, Julie A.; Wodicka, Lisa; Del Rio, Jo A.; Tennant, Richard; Tynan, Wendy; Broide, Ron S.; Helton, Rob; Stoveken, Barbara S.; Winrow, Christopher; Lockhart, Daniel J.; Reilly, John F.; Young, Warren G.; Bloom, Floyd E.; Lockhart, David J.; Barlow, Carrolee

    2005-01-01

    The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional “imprint” consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anterior–posterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene expression patterns in adult structures. We also observed a significant number of embryonic patterning and homeobox genes with region-specific expression in the adult nervous system. The relationships between global expression patterns for different anatomical regions and the nature of the observed region-specific genes suggest that the adult brain retains a degree of overall gene expression established during embryogenesis that is important for regional specificity and the functional relationships between regions in the adult. The complete collection of extensively annotated gene expression data along with data mining and visualization tools have been made available on a publicly accessible web site (www.barlow-lockhart-brainmapnimhgrant.org). PMID:16002470

  16. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes

    PubMed Central

    Reik, Wolf; Constância, Miguel; Fowden, Abigail; Anderson, Neil; Dean, Wendy; Ferguson-Smith, Anne; Tycko, Benjamin; Sibley, Colin

    2003-01-01

    The placenta has evolved in eutherian mammals primarily to provide nutrients for the developing fetus. The genetic control of the regulation of supply and demand for maternal nutrients is not understood. In this review we argue that imprinted genes have central roles in controlling both the fetal demand for, and the placental supply of, maternal nutrients. Recent studies on Igf2 (insulin-like growth factor 2) knockout mouse models provide experimental support for this hypothesis. These show effects on placental transport capacity consistent with a role of IGF-II in modulating both the placental supply and fetal demand for nutrients. Imprinting of genes with such functions may have coevolved with the placenta and new evidence suggests that transporter proteins, as well as the regulators themselves, may also be imprinted. These data and hypotheses are important, as deregulation of supply and demand affects fetal growth and has long term consequences for health in mammals both in the neonatal period and, as a result of fetal programming, in adulthood. PMID:12562908

  17. Genome-wide histone state profiling of fibroblasts from the opossum, Monodelphis domestica, identifies the first marsupial-specific imprinted gene

    PubMed Central

    2014-01-01

    Background Imprinted genes have been extensively documented in eutherian mammals and found to exhibit significant interspecific variation in the suites of genes that are imprinted and in their regulation between tissues and developmental stages. Much less is known about imprinted loci in metatherian (marsupial) mammals, wherein studies have been limited to a small number of genes previously known to be imprinted in eutherians. We describe the first ab initio search for imprinted marsupial genes, in fibroblasts from the opossum, Monodelphis domestica, based on a genome-wide ChIP-seq strategy to identify promoters that are simultaneously marked by mutually exclusive, transcriptionally opposing histone modifications. Results We identified a novel imprinted gene (Meis1) and two additional monoallelically expressed genes, one of which (Cstb) showed allele-specific, but non-imprinted expression. Imprinted vs. allele-specific expression could not be resolved for the third monoallelically expressed gene (Rpl17). Transcriptionally opposing histone modifications H3K4me3, H3K9Ac, and H3K9me3 were found at the promoters of all three genes, but differential DNA methylation was not detected at CpG islands at any of these promoters. Conclusions In generating the first genome-wide histone modification profiles for a marsupial, we identified the first gene that is imprinted in a marsupial but not in eutherian mammals. This outcome demonstrates the practicality of an ab initio discovery strategy and implicates histone modification, but not differential DNA methylation, as a conserved mechanism for marking imprinted genes in all therian mammals. Our findings suggest that marsupials use multiple epigenetic mechanisms for imprinting and support the concept that lineage-specific selective forces can produce sets of imprinted genes that differ between metatherian and eutherian lines. PMID:24484454

  18. H19 controls reactivation of the imprinted gene network during muscle regeneration.

    PubMed

    Martinet, Clémence; Monnier, Paul; Louault, Yann; Benard, Matthieu; Gabory, Anne; Dandolo, Luisa

    2016-03-15

    The H19 locus controls fetal growth by regulating expression of several genes from the imprinted gene network (IGN). H19 is fully repressed after birth, except in skeletal muscle. Using loss-of-function H19(Δ3) mice, we investigated the function of H19 in adult muscle. Mutant muscles display hypertrophy and hyperplasia, with increased Igf2 and decreased myostatin (Mstn) expression. Many imprinted genes are expressed in muscle stem cells or satellite cells. Unexpectedly, the number of satellite cells was reduced by 50% in H19(Δ3) muscle fibers. This reduction occurred after postnatal day 21, suggesting a link with their entry into quiescence. We investigated the biological function of these mutant satellite cells in vivo using a regeneration assay induced by multiple injections of cardiotoxin. Surprisingly, despite their reduced number, the self-renewal capacity of these cells is fully retained in the absence of H19. In addition, we observed a better regeneration potential of the mutant muscles, with enhanced expression of several IGN genes and genes from the IGF pathway. PMID:26980793

  19. Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma.

    PubMed

    Shu, Jingmin; Li, Lihua; Sarver, Anne E; Pope, Emily A; Varshney, Jyotika; Thayanithy, Venugopal; Spector, Logan; Largaespada, David A; Steer, Clifford J; Subramanian, Subbaya

    2016-04-19

    Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes. PMID:26802029

  20. Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma

    PubMed Central

    Shu, Jingmin; Li, Lihua; Sarver, Anne E.; Pope, Emily A.; Varshney, Jyotika; Thayanithy, Venugopal; Spector, Logan; Largaespada, David A.; Steer, Clifford J.; Subramanian, Subbaya

    2016-01-01

    Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes. PMID:26802029

  1. Activation of tumor suppressor p53 gene expression by magnetic thymine-imprinted chitosan nanoparticles.

    PubMed

    Lee, Mei-Hwa; Thomas, James L; Chen, Jian-Zhou; Jan, Jeng-Shiung; Lin, Hung-Yin

    2016-02-01

    Chitosan is a natural biodegradable polysaccharide that has been used to enhance gene delivery, owing to the ease with which chitosan nanoparticles enter the nucleus of cells. To study the effects of nuclear delivery of telomeric gene sequences, which contain thymine, we formed magnetic thymine-imprinted chitosan nanoparticles (TIPs) by the precipitation of chitosan, mixed with thymine and magnetic nanoparticles (to aid in separations). The mean size of the TIPS was 116 ± 18 nm; the dissociation constant for thymine was 21.8 mg mL(-1). We then treated human hepatocellular carcinoma (HepG2) with TIPs nanoparticles bearing bound thymine or a bound telomeric DNA sequence. The expression of the tumor suppressor p53 gene increased when TIPs were applied and decreased when telomere-bound TIPs were applied. PMID:26693943

  2. An AP endonuclease functions in active DNA demethylation and gene imprinting in Arabidopsis [corrected].

    PubMed

    Li, Yan; Córdoba-Cañero, Dolores; Qian, Weiqiang; Zhu, Xiaohong; Tang, Kai; Zhang, Huiming; Ariza, Rafael R; Roldán-Arjona, Teresa; Zhu, Jian-Kang

    2015-01-01

    Active DNA demethylation in plants occurs through base excision repair, beginning with removal of methylated cytosine by the ROS1/DME subfamily of 5-methylcytosine DNA glycosylases. Active DNA demethylation in animals requires the DNA glycosylase TDG or MBD4, which functions after oxidation or deamination of 5-methylcytosine, respectively. However, little is known about the steps following DNA glycosylase action in the active DNA demethylation pathways in plants and animals. We show here that the Arabidopsis APE1L protein has apurinic/apyrimidinic endonuclease activities and functions downstream of ROS1 and DME. APE1L and ROS1 interact in vitro and co-localize in vivo. Whole genome bisulfite sequencing of ape1l mutant plants revealed widespread alterations in DNA methylation. We show that the ape1l/zdp double mutant displays embryonic lethality. Notably, the ape1l+/-zdp-/- mutant shows a maternal-effect lethality phenotype. APE1L and the DNA phosphatase ZDP are required for FWA and MEA gene imprinting in the endosperm and are important for seed development. Thus, APE1L is a new component of the active DNA demethylation pathway and, together with ZDP, regulates gene imprinting in Arabidopsis. PMID:25569774

  3. Genomic Imprinting in Mammals

    PubMed Central

    Barlow, Denise P.

    2014-01-01

    Genomic imprinting affects a subset of genes in mammals and results in a monoallelic, parental-specific expression pattern. Most of these genes are located in clusters that are regulated through the use of insulators or long noncoding RNAs (lncRNAs). To distinguish the parental alleles, imprinted genes are epigenetically marked in gametes at imprinting control elements through the use of DNA methylation at the very least. Imprinted gene expression is subsequently conferred through lncRNAs, histone modifications, insulators, and higher-order chromatin structure. Such imprints are maintained after fertilization through these mechanisms despite extensive reprogramming of the mammalian genome. Genomic imprinting is an excellent model for understanding mammalian epigenetic regulation. PMID:24492710

  4. Imprints of Natural Selection Along Environmental Gradients in Phenology-Related Genes of Quercus petraea

    PubMed Central

    Alberto, Florian J.; Derory, Jérémy; Boury, Christophe; Frigerio, Jean-Marc; Zimmermann, Niklaus E.; Kremer, Antoine

    2013-01-01

    We explored single nucleotide polymorphism (SNP) variation in candidate genes for bud burst from Quercus petraea populations sampled along gradients of latitude and altitude in Western Europe. SNP diversity was monitored for 106 candidate genes, in 758 individuals from 32 natural populations. We investigated whether SNP variation reflected the clinal pattern of bud burst observed in common garden experiments. We used different methods to detect imprints of natural selection (FST outlier, clinal variation at allelic frequencies, association tests) and compared the results obtained for the two gradients. FST outlier SNPs were found in 15 genes, 5 of which were common to both gradients. The type of selection differed between the two gradients (directional or balancing) for 3 of these 5. Clinal variations were observed for six SNPs, and one cline was conserved across both gradients. Association tests between the phenotypic or breeding values of trees and SNP genotypes identified 14 significant associations, involving 12 genes. The results of outlier detection on the basis of population differentiation or clinal variation were not very consistent with the results of association tests. The discrepancies between these approaches may reflect the different hierarchical levels of selection considered (inter- and intrapopulation selection). Finally, we obtained evidence for convergent selection (similar for gradients) and clinal variation for a few genes, suggesting that comparisons between parallel gradients could be used to screen for major candidate genes responding to natural selection in trees. PMID:23934884

  5. Functional Genomic Approaches for the Study of Fetal/Placental Development in Swine with Special Emphasis on Imprinted Genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The overall focus of this chapter will be the application of functional genomic approaches for the study of the imprinted gene family in swine. While there are varied definitions of “functional genomics” in general they focus on the application of genomic approaches such as DNA microarrays, single n...

  6. Alterations in methylation and expression levels of imprinted genes H19 and Igf2 in the fetuses of diabetic mice.

    PubMed

    Shao, Wei-Juan; Tao, Ling-Yun; Gao, Cheng; Xie, Jian-Yun; Zhao, Ru-Qian

    2008-08-01

    The study aimed to reveal alterations in expression and methylation levels of the growth-related imprinted genes H19 and Igf2 in fetuses of diabetic mice. Diabetes was induced in female mice by intraperitoneal injection of streptozotocin. DNA and total RNA were extracted from fetuses obtained from diabetic and control dams on embryonic day (E) 14. Real-time RT-PCR analysis revealed that the mRNA expression of Igf2 in fetuses from diabetic mice was 0.65-fold of the control counterparts. Bisulfite genomic sequencing demonstrated that the methylation level of the H19-Igf2 imprint control region was 19.1% higher in diabetic fetuses than in those of control dams. In addition, the body weight of pups born to diabetic dams was 26.5% lower than that of the control group. The results indicate that maternal diabetes can affect fetal development by means of altered expression of imprinted genes. The modified genomic DNA methylation status of imprinting genes may account for the change in gene expression. PMID:18724775

  7. Tissue-specific imprinting of the mouse insulin-like growth factor II receptor gene correlates with differential allele-specific DNA methylation.

    PubMed

    Hu, J F; Oruganti, H; Vu, T H; Hoffman, A R

    1998-02-01

    Imprinted genes may be expressed uniparentally in a tissue- and development-specific manner. The insulin-like growth factor II receptor gene (Igf2r), one of the first imprinted genes to be identified, is an attractive candidate for studying the molecular mechanism of genomic imprinting because it is transcribed monoallelically in the mouse but biallelically in humans. To identify the factors that control genomic imprinting, we examined allelic expression of Igf2r at different ages in interspecific mice. We found that Igf2r is not always monoallelically expressed. Paternal imprinting of Igf2r is maintained in peripheral tissues, including liver, kidney, heart, spleen, intestine, bladder, skin, bone, and skeletal muscle. However, in central nervous system (CNS), Igf2r is expressed from both parental alleles. Southern analysis of the Igf2r promoter (region 1) revealed that, outside of the CNS where Igf2r is monoallelically expressed, the suppressed paternal allele is fully methylated while the expressed maternal allele is completely unmethylated. In CNS, however, both parental alleles are unmethylated in region 1. The importance of DNA methylation in the maintenance of the genomic imprint was also confirmed by the finding that Igf2r imprinting was relaxed by 5-azacytidine treatment. The correlation between genomic imprinting and allelic Igf2r methylation in CNS and other tissues thus suggests that the epigenetic modification in the promoter region may function as one of the major factors in maintaining the monoallelic expression of Igf2r. PMID:9482664

  8. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15.

    PubMed Central

    Matsuoka, S; Thompson, J S; Edwards, M C; Bartletta, J M; Grundy, P; Kalikin, L M; Harper, J W; Elledge, S J; Feinberg, A P

    1996-01-01

    Parental origin-specific alterations of chromosome 11p15 in human cancer suggest the involvement of one or more maternally expressed imprinted genes involved in embryonal tumor suppression and the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). The gene encoding cyclin-dependent kinase inhibitor p57KIP2, whose overexpression causes G1 phase arrest, was recently cloned and mapped to this band. We find that the p57KIP2 gene is imprinted, with preferential expression of the maternal allele. However, the imprint is not absolute, as the paternal allele is also expressed at low levels in most tissues, and at levels comparable to the maternal allele in fetal brain and some embryonal tumors. The biochemical function, chromosomal location, and imprinting of the p57KIP2 gene match the properties predicted for a tumor suppressor gene at 11p15.5. However, as the p57KIP2 gene is 500 kb centromeric to the gene encoding insulin-like growth factor 2, it is likely to be part of a large domain containing other imprinted genes. Thus, loss of heterozygosity or loss of imprinting might simultaneously affect several genes at this locus that together contribute to tumor and/or growth- suppressing functions that are disrupted in BWS and embryonal tumors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8610162

  9. Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood

    PubMed Central

    Li, Yue; Xie, Changchun; Murphy, Susan K.; Skaar, David; Nye, Monica; Vidal, Adriana C.; Cecil, Kim M.; Dietrich, Kim N.; Puga, Alvaro; Jirtle, Randy L.; Hoyo, Cathrine

    2015-01-01

    Background: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. Objectives: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. Methods: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. Results: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = –0.0014; 95% CI: –0.0023, –0.0005, p = 0.002), stronger in males (β = –0.0024; 95% CI: –0.0038, –0.0009, p = 0.003) than in females (β = –0.0009; 95% CI: –0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = –0.0013; 95% CI: –0.0023, –0.0003, p = 0.01) DMR methylation, but primarily in females, (β = –0.0017; 95% CI: –0.0029, –0.0006, p = 0.005) rather than in males, (β = –0.0004; 95% CI: –0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from

  10. Dynamic Expression of Imprinted Genes Associates with Maternally Controlled Nutrient Allocation during Maize Endosperm Development[W][OPEN

    PubMed Central

    Xin, Mingming; Yang, Ruolin; Li, Guosheng; Chen, Hao; Laurie, John; Ma, Chuang; Wang, Dongfang; Yao, Yingyin; Larkins, Brian A.; Sun, Qixin; Yadegari, Ramin; Wang, Xiangfeng; Ni, Zhongfu

    2013-01-01

    In angiosperms, the endosperm provides nutrients for embryogenesis and seed germination and is the primary tissue where gene imprinting occurs. To identify the imprintome of early developing maize (Zea mays) endosperm, we performed high-throughput transcriptome sequencing of whole kernels at 0, 3, and 5 d after pollination (DAP) and endosperms at 7, 10, and 15 DAP, using B73 by Mo17 reciprocal crosses. We observed gradually increased expression of paternal transcripts in 3- and 5-DAP kernels. In 7-DAP endosperm, the majority of the genes tested reached a 2:1 maternal versus paternal ratio, suggesting that paternal genes are nearly fully activated by 7 DAP. A total of 116, 234, and 63 genes exhibiting parent-specific expression were identified at 7, 10, and 15 DAP, respectively. The largest proportion of paternally expressed genes was at 7 DAP, mainly due to the significantly deviated parental allele expression ratio of these genes at this stage, while nearly 80% of the maternally expressed genes (MEGs) were specific to 10 DAP and were primarily attributed to sharply increased expression levels compared with the other stages. Gene ontology enrichment analysis of the imprinted genes suggested that 10-DAP endosperm-specific MEGs are involved in nutrient uptake and allocation and the auxin signaling pathway, coincident with the onset of starch and storage protein accumulation. PMID:24058158

  11. Mammalian-specific genomic functions: Newly acquired traits generated by genomic imprinting and LTR retrotransposon-derived genes in mammals

    PubMed Central

    KANEKO-ISHINO, Tomoko; ISHINO, Fumitoshi

    2015-01-01

    Mammals, including human beings, have evolved a unique viviparous reproductive system and a highly developed central nervous system. How did these unique characteristics emerge in mammalian evolution, and what kinds of changes did occur in the mammalian genomes as evolution proceeded? A key conceptual term in approaching these issues is “mammalian-specific genomic functions”, a concept covering both mammalian-specific epigenetics and genetics. Genomic imprinting and LTR retrotransposon-derived genes are reviewed as the representative, mammalian-specific genomic functions that are essential not only for the current mammalian developmental system, but also mammalian evolution itself. First, the essential roles of genomic imprinting in mammalian development, especially related to viviparous reproduction via placental function, as well as the emergence of genomic imprinting in mammalian evolution, are discussed. Second, we introduce the novel concept of “mammalian-specific traits generated by mammalian-specific genes from LTR retrotransposons”, based on the finding that LTR retrotransposons served as a critical driving force in the mammalian evolution via generating mammalian-specific genes. PMID:26666304

  12. Towards the cloning of imprinted genes in the Prader-Willi/Angelman region of chromosome 15q11-q13

    SciTech Connect

    Nakao, M.; Sutcliffe, J.S.; Beaudet, A.L.

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct clinical phenotypes resulting from paternal and maternal deficiencies respectively in human chromosome 15q11-q13. The data suggest the presence of oppositely imprinted genes in the region, and the gene for small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) has been identified as a candidate gene for PWS. Previous strategies for positional cloning identified a number of transcripts from the PWS/AS region, and two of them, PAR-5 (D15S226E) and PAR-1 (D15S227E), are paternally expressed in cultured human cells from patients deleted for 15q11-q13 as is SNRPN. Cosmid contig maps have been developed from the following YACs (contained loci in parentheses): 307A12 (D15S13), 457B4 (SNRPN), 132D4 (D15S10), A229A2, and 378A12 (D15S113), to facilitate molecular studies of PWS and AS. Exon trapping has been employed to isolate putative exons from these overlapping cosmids. Two trapped fragments from the D15S113 region and one fragment from the SNRPN region has been isolated. Sequence information is available for all of the fragments. In addition to imprinting analysis in cultured human cells, we have developed a method to detect imprinting in mouse and human using a GC-clamped denaturing gradient gel electrophoresis strategy, in combination with reverse transcription-polymerase chain reaction. The imprinting analyses of putative exons are in progress to investigate their possible candidacy for involvement in PWS or AS phenotypes.

  13. mRNA Levels of Imprinted Genes in Bovine In Vivo Oocytes, Embryos and Cross Species Comparisons with Humans, Mice and Pigs

    PubMed Central

    Jiang, Zongliang; Dong, Hong; Zheng, Xinbao; Marjani, Sadie L.; Donovan, David M.; Chen, Jingbo; Tian, Xiuchun (Cindy)

    2015-01-01

    Twenty-six imprinted genes were quantified in bovine in vivo produced oocytes and embryos using RNA-seq. Eighteen were detectable and their transcriptional patterns were: largely decreased (MEST and PLAGL1); first decreased and then increased (CDKN1C and IGF2R); peaked at a specific stage (PHLDA2, SGCE, PEG10, PEG3, GNAS, MEG3, DGAT1, ASCL2, NNAT, and NAP1L5); or constantly low (DIRAS3, IGF2, H19 and RTL1). These patterns reflect mRNAs that are primarily degraded, important at a specific stage, or only required at low quantities. The mRNAs for several genes were surprisingly abundant. For instance, transcripts for the maternally imprinted MEST and PLAGL1, were high in oocytes and could only be expressed from the maternal allele suggesting that their genomic imprints were not yet established/recognized. Although the mRNAs detected here were likely biallelically transcribed before the establishment of imprinted expression, the levels of mRNA during these critical stages of development have important functional consequences. Lastly, we compared these genes to their counterparts in mice, humans and pigs. Apart from previously known differences in the imprinting status, the mRNA levels were different among these four species. The data presented here provide a solid reference for expression profiles of imprinted genes in embryos produced using assisted reproductive biotechnologies. PMID:26638780

  14. Active and Repressive Chromatin Are Interspersed without Spreading in an Imprinted Gene Cluster in the Mammalian Genome

    PubMed Central

    Regha, Kakkad; Sloane, Mathew A.; Huang, Ru; Pauler, Florian M.; Warczok, Katarzyna E.; Melikant, Balázs; Radolf, Martin; Martens, Joost H.A.; Schotta, Gunnar; Jenuwein, Thomas; Barlow, Denise P.

    2010-01-01

    SUMMARY The Igf2r imprinted cluster is an epigenetic silencing model in which expression of a ncRNA silences multiple genes in cis. Here, we map a 250 kb region in mouse embryonic fibroblast cells to show that histone modifications associated with expressed and silent genes are mutually exclusive and localized to discrete regions. Expressed genes were modified at promoter regions by H3K4me3 + H3K4me2 + H3K9Ac and on putative regulatory elements flanking active promoters by H3K4me2 + H3K9Ac. Silent genes showed two types of nonoverlapping profile. One type spread over large domains of tissue-specific silent genes and contained H3K27me3 alone. A second type formed localized foci on silent imprinted gene promoters and a nonexpressed pseudogene and contained H3K9me3 + H4K20me3 ± HP1. Thus, mammalian chromosome arms contain active chromatin interspersed with repressive chromatin resembling the type of heterochromatin previously considered a feature of centromeres, telomeres, and the inactive X chromosome. PMID:17679087

  15. Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene.

    PubMed

    Fridman, C; Hosomi, N; Varela, M C; Souza, A H; Fukai, K; Koiffmann, C P

    2003-06-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11-q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader-Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF-SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hypopigmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region. PMID:12749060

  16. Imprinted genes and transpositions: epigenomic targets for low dose radiation effects. Final report

    SciTech Connect

    Jirtle, Randy L.

    2012-10-11

    The overall hypothesis of this grant application is that low dose ionizing radiation (LDIR) elicits adaptive responses in part by causing heritable DNA methylation changes in the epigenome. This novel postulate was tested by determining if the level of DNA methylation at the Agouti viable yellow (A{sup vy}) metastable locus is altered, in a dose-dependent manner, by low dose radiation exposure (<10 cGy) during early gestation. This information is particularly important to ascertain given the increased use of CT scans in disease diagnosis, increased number of people predicted to live and work in space, and the present concern about radiological terrorism. We showed for the first time that LDIR significantly increased DNA methylation at the A{sup vy} locus in a sex-specific manner (p=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 cGy and 7.6 cGy with maximum effects at 1.4 cGy and 3.0 cGy (p<0.01). Offspring coat color was concomitantly shifted towards pseudoagouti (p<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring (p<0.05). Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic Avy mouse model epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. Our findings not only have significant implications concerning the mechanism of hormesis, but they also emphasize the potential importance of this phenomenon in determining human risk at low radiation doses. Since the epigenetic regulation of genes varies markedly between species, the effect of LDIR on other epigenetically labile genes (e.g. imprinted genes) in

  17. Evolution and function of genomic imprinting in plants

    PubMed Central

    Rodrigues, Jessica A.; Zilberman, Daniel

    2015-01-01

    Genomic imprinting, an inherently epigenetic phenomenon defined by parent of origin-dependent gene expression, is observed in mammals and flowering plants. Genome-scale surveys of imprinted expression and the underlying differential epigenetic marks have led to the discovery of hundreds of imprinted plant genes and confirmed DNA and histone methylation as key regulators of plant imprinting. However, the biological roles of the vast majority of imprinted plant genes are unknown, and the evolutionary forces shaping plant imprinting remain rather opaque. Here, we review the mechanisms of plant genomic imprinting and discuss theories of imprinting evolution and biological significance in light of recent findings. PMID:26680300

  18. Genomic imprinting and cancer.

    PubMed

    Brenton, J D; Viville, S; Surani, M A

    1995-01-01

    Imprinting is vital for normal development, and disruption of imprinting mechanisms on syntenic chromosomes gives very similar phenotypes in mouse and humans. In addition, disruption of normal imprinting provides a plausible explanation for preferential LOH in some embryonal tumours. Moreover, there is evidence that in Wilms' tumour, dysregulation of specific imprinted genes may give rise to the cancer phenotype. Many more questions regarding genomic imprinting need to be answered before the associations described in this review can be properly understood. The most basic issues, such as when and how the imprint is established, can still only be speculated upon. Further study of new imprinted genes and the relationship between their domains and differential replication may show us higher control mechanisms than methylation alone. It remains to be seen if these epigenetic modifications are amenable to therapeutic change in the treatment of inherited syndromes and cancer, or if they can be used to assess individuals at risk of disease. Until then it is probably unwise to speculate on a single unifying theory that explains why a subset of the genome shows such a peculiar non-Mendelian form of inheritance. PMID:8718517

  19. Environmental Influences on Genomic Imprinting

    PubMed Central

    Kappil, Maya; Lambertini, Luca; Chen, Jia

    2015-01-01

    Genomic imprinting refers to the epigenetic mechanism that results in the mono-allelic expression of a subset of genes in a parent-of-origin manner. These haploid genes are highly active in the placenta and are functionally implicated in the appropriate development of the fetus. Furthermore, the epigenetic marks regulating imprinted expression patterns are established early in development. These characteristics make genomic imprinting a potentially useful biomarker for environmental insults, especially during the in utero or early development stages, and for health outcomes later in life. Herein, we critically review the current literature regarding environmental influences on imprinted genes and summarize findings that suggest that imprinted loci are sensitive to known teratogenic agents, such as alcohol and tobacco, as well as less established factors with the potential to manipulate the in utero environment, including assisted reproductive technology. Finally, we discuss the potential of genomic imprinting to serve as an environmental sensor during early development. PMID:26029493

  20. The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources

    PubMed Central

    Tunster, S.J.; Creeth, H.D.J.; John, R.M.

    2016-01-01

    Imprinted genes, which are expressed from a single parental allele in response to epigenetic marks first established in the germline, function in a myriad of processes to regulate mammalian development. Recent work suggests that imprinted genes may regulate the signalling function of the placenta by modulating the size of the endocrine compartment. Here we provide in vivo evidence that this hypothesis is well founded. Elevated expression of the imprinted Pleckstrin homology-like domain, family a, member 2 (Phlda2) gene drives a reduction of the spongiotrophoblast endocrine compartment, diminished placental glycogen and asymmetric foetal growth restriction. Using both loss-of-function and gain-in-expression mouse models, here we further show that Phlda2 exclusively modulates the spongiotrophoblast compartment of the placenta without significantly altering the composition of the trophoblast giant cell endocrine lineages that share a common progenitor with this lineage. Additionally, we show that Phlda2 loss-of-function placentae contain nearly three times more placental glycogen than non-transgenic placentae. Remarkably, relative to a fully wild type scenario, wild type placentae also accumulate excessive glycogen. While loss-of-function of Phlda2 increased both placental weight and placental glycogen, the weight of both mutant and non-transgenic fetuses was lower than that found in a fully wild type scenario indicating that excessive glycogen accumulation comes at the cost of foetal growth. This work firstly highlights a novel signalling function for the spongiotrophoblast in stimulating the global accumulation of placental glycogen. Furthermore, this work suggests that Phlda2 manipulates the placenta's demands for maternal resources, a process that must be tightly regulated by epigenetic marks to ensure optimal foetal growth. PMID:26476147

  1. The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources.

    PubMed

    Tunster, S J; Creeth, H D J; John, R M

    2016-01-01

    Imprinted genes, which are expressed from a single parental allele in response to epigenetic marks first established in the germline, function in a myriad of processes to regulate mammalian development. Recent work suggests that imprinted genes may regulate the signalling function of the placenta by modulating the size of the endocrine compartment. Here we provide in vivo evidence that this hypothesis is well founded. Elevated expression of the imprinted Pleckstrin homology-like domain, family a, member 2 (Phlda2) gene drives a reduction of the spongiotrophoblast endocrine compartment, diminished placental glycogen and asymmetric foetal growth restriction. Using both loss-of-function and gain-in-expression mouse models, here we further show that Phlda2 exclusively modulates the spongiotrophoblast compartment of the placenta without significantly altering the composition of the trophoblast giant cell endocrine lineages that share a common progenitor with this lineage. Additionally, we show that Phlda2 loss-of-function placentae contain nearly three times more placental glycogen than non-transgenic placentae. Remarkably, relative to a fully wild type scenario, wild type placentae also accumulate excessive glycogen. While loss-of-function of Phlda2 increased both placental weight and placental glycogen, the weight of both mutant and non-transgenic fetuses was lower than that found in a fully wild type scenario indicating that excessive glycogen accumulation comes at the cost of foetal growth. This work firstly highlights a novel signalling function for the spongiotrophoblast in stimulating the global accumulation of placental glycogen. Furthermore, this work suggests that Phlda2 manipulates the placenta's demands for maternal resources, a process that must be tightly regulated by epigenetic marks to ensure optimal foetal growth. PMID:26476147

  2. Genomic imprinting and cancer.

    PubMed Central

    Joyce, J A; Schofield, P N

    1998-01-01

    Genomic imprinting is the phenomenon by which individual alleles of certain genes are expressed differentially according to their parent of origin. The alleles appear to be differentially marked during gametogenesis or during the early part of development. This mark is heritable but reversible from generation to generation, implying a stable epigenetic modification. Approximately 25 imprinted genes have been identified to date, and dysregulation of a number of these has been implicated in tumour development. The normal physiological role of many imprinted genes is in the control of cell proliferation and fetal growth, indicating potential mechanisms of action in tumour formation. Both dominant and recessive modes of action have been postulated for the role of imprinted genes in neoplasia, as a result of effective gene dosage alterations by epigenetic modification of the normal pattern of allele specific transcription. The aim of this review is to assess the importance of imprinted genes in generating tumours and to discuss the implications for novel mechanisms of transforming mutation. PMID:9893743

  3. NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms

    PubMed Central

    Yu, Yinhua; Mao, Weiqun; Wang, Yan; Baggerly, Keith; Wang, Ying; Marquez, Rebecca T.; Bedi, Anuja; Liu, Jinsong; Fishman, David; Lu, Zhen; Bast, Robert C.

    2016-01-01

    NDN is a maternally imprinted gene consistently expressed in normal ovarian epithelium, is dramatically downregulated in the majority of ovarian cancers. Little or no NDN expression could be detected in 73% of 351 epithelial ovarian cancers. NDN was also downregulated in 10 ovarian cancer cell lines with total loss in 6 of 10. Re-expression of NDN decreased Bcl-2 levels and induced apoptosis, which significantly inhibited ovarian cancer cell growth in cell culture and in xenografts. In addition, re-expression of NDN inhibited cell migration by decreasing actin stress fiber and focal adhesion complex formation through deactivation of Src, FAK and RhoA. Loss of NDN expression in ovarian cancers could be attributed to LOH in 28% of 18 informative cases and to hypermethylation of CpG sites 1 and 2 of NDN promoter in 23% and 30% of 43 ovarian cancers, respectively. Promoter hypermethylation was also found in 5 of 10 ovarian cancer cell lines. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored NDN expression in 4 of 7 cell lines with enhanced promoter methylation levels. These observations support the conclusion that NDN is an imprinted tumor suppressor gene which affects cancer cell motility, invasion and growth and that its loss of function in ovarian cancer can be caused by both genetic and epigenetic mechanisms. PMID:26689988

  4. Methylation of KvDMR1 involved in regulating the imprinting of CDKN1C gene in cattle.

    PubMed

    Wang, Mengnan; Li, Dongjie; Zhang, Mingyue; Yang, Wenzhi; Cui, Yali; Li, Shijie

    2015-08-01

    The CDKN1C gene encodes a cyclin-dependent kinase inhibitor and is one of the key genes involved in the development of Beckwith-Wiedemann syndrome and cancer. In this study, using a direct sequencing approach based on a single nucleotide polymorphism (SNP) at genomic DNA and cDNA levels, we show that CDKN1C exhibits monoallelic expression in all seven studied organs (heart, liver, spleen, lung, kidney, muscle and subcutaneous fat) in cattle. To investigate how methylation regulates imprinting of CDKN1C in cattle, allele-specific methylation patterns in two putative differential methylation regions (DMRs), the CDKN1C DMR and KvDMR1, were analyzed in three tissues (liver, spleen and lung) using bisulfite sequencing PCR. Our results show that in the CDKN1C DMR both parental alleles were unmethylated in all three analyzed tissues. In contrast, KvDMR1 was differentially methylated between the two parental alleles in the same tissues. Statistical analysis showed that there is a significant difference in the methylation level between the two parental alleles (P < 0.01), confirming that this region is the DMR of KvDMR1 and that it may be correlated with CDKN1C imprinting. PMID:26059028

  5. Activation of an imprinted allele of the insulin-like growth factor II gene implicated in rhabdomyosarcoma.

    PubMed Central

    Zhan, S; Shapiro, D N; Helman, L J

    1994-01-01

    The insulin-like growth factor II (IGF2) gene is exclusively silent at the maternal allele in the mouse as well as in normal human tissues and is expressed at a high level in rhabdomyosarcoma (RMS). We report here that the normally imprinted allele of the IGF2 gene is activated in RMS tumors as well as in one RMS cell line. Since overexpression of IGF2 has been shown to be important in the pathogenesis of RMS, our data suggest that loss of imprinting (LOI) may lead to overexpression of IGF2 and play an important role in the onset of RMS. Furthermore, embryonal RMS usually has loss of heterozygosity (LOH) with paternal disomy of the IGF2 locus. One informative embryonal RMS tumor evaluated in this study was heterozygous at the IGF2 allele and had LOI, raising the possibility that LOI may be the functional equivalent of LOH in this tumor with both events leading to overexpression of IGF2. Images PMID:8040287

  6. Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio.

    PubMed

    Bodian, Dale L; Solomon, Benjamin D; Khromykh, Alina; Thach, Dzung C; Iyer, Ramaswamy K; Link, Kathleen; Baker, Robin L; Baveja, Rajiv; Vockley, Joseph G; Niederhuber, John E

    2014-11-01

    Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother-father-proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith-Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants. PMID:25614875

  7. Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio

    PubMed Central

    Bodian, Dale L; Solomon, Benjamin D; Khromykh, Alina; Thach, Dzung C; Iyer, Ramaswamy K; Link, Kathleen; Baker, Robin L; Baveja, Rajiv; Vockley, Joseph G; Niederhuber, John E

    2014-01-01

    Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother–father–proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith–Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants. PMID:25614875

  8. Sex- and Diet-Specific Changes of Imprinted Gene Expression and DNA Methylation in Mouse Placenta under a High-Fat Diet

    PubMed Central

    Tost, Jörg; Karimi, Mohsen; Mayeur, Sylvain; Lesage, Jean; Boudadi, Elsa; Gross, Marie-Sylvie; Taurelle, Julien; Vigé, Alexandre; Breton, Christophe; Reusens, Brigitte; Remacle, Claude; Vieau, Didier; Ekström, Tomas J.; Jais, Jean-Philippe; Junien, Claudine

    2010-01-01

    Background Changes in imprinted gene dosage in the placenta may compromise the prenatal control of nutritional resources. Indeed monoallelic behaviour and sensitivity to changes in regional epigenetic state render imprinted genes both vulnerable and adaptable. Methods and Findings We investigated whether a high-fat diet (HFD) during pregnancy modified the expression of imprinted genes and local and global DNA methylation patterns in the placenta. Pregnant mice were fed a HFD or a control diet (CD) during the first 15 days of gestation. We compared gene expression patterns in total placenta homogenates, for male and female offspring, by the RT-qPCR analysis of 20 imprinted genes. Sexual dimorphism and sensitivity to diet were observed for nine genes from four clusters on chromosomes 6, 7, 12 and 17. As assessed by in situ hybridization, these changes were not due to variation in the proportions of the placental layers. Bisulphite-sequencing analysis of 30 CpGs within the differentially methylated region (DMR) of the chromosome 17 cluster revealed sex- and diet-specific differential methylation of individual CpGs in two conspicuous subregions. Bioinformatic analysis suggested that these differentially methylated CpGs might lie within recognition elements or binding sites for transcription factors or factors involved in chromatin remodelling. Placental global DNA methylation, as assessed by the LUMA technique, was also sexually dimorphic on the CD, with lower methylation levels in male than in female placentae. The HFD led to global DNA hypomethylation only in female placenta. Bisulphite pyrosequencing showed that neither B1 nor LINE repetitive elements could account for these differences in DNA methylation. Conclusions A HFD during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes important in the control of many cellular, metabolic and physiological functions

  9. Epigenetic consequences of artificial reproductive technologies to the bovine imprinted genes SNRPN, H19/IGF2, and IGF2R

    PubMed Central

    Smith, Lawrence C.; Therrien, Jacinthe; Filion, France; Bressan, Fabiana; Meirelles, Flávio V.

    2015-01-01

    Animal breeders have made widespread use of assisted reproductive technologies to accelerate genetic improvement programs aimed at obtaining more, better and cheaper food products. Selection approaches have traditionally focused on Mendel’s laws of inheritance using parental phenotypic characteristics and quantitative genetics approaches to choose the best parents for the next generation, regardless of their gender. However, apart from contributing DNA sequence variants, male and female gametes carry parental-specific epigenetic marks that play key roles during pre- and post-natal development and growth of the offspring. We herein review the epigenetic anomalies that are associated with artificial reproductive technologies in current use in animal breeding programs. For instance, we demonstrate that bovine embryos and fetuses derived by in vitro culture and somatic cell nuclear transfer show epigenetic anomalies in the differentially methylated regions controlling the expression of some imprinted genes. Although these genomic imprinting errors are undetected in the somatic tissues after birth, further research is warranted to examine potential germ cell transmission of epimutations and the potential risks of reproducing cattle using artificial reproductive technologies. PMID:25763013

  10. mRNA levels of imprinted genes in bovine in vivo oocytes, embryos and cross species comparisons in humans, mice and pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Twenty-six confirmed imprinted genes in the bovine were quantified in in vivo produced oocytes and embryos. Eighteen were detectable and their transcriptional abundance were categorized into five patterns: largely decreased (MEST and PLAGL1); first decreased and then increased (CDKN1C and IGF2R); p...

  11. The landscape of genomic imprinting across diverse adult human tissues.

    PubMed

    Baran, Yael; Subramaniam, Meena; Biton, Anne; Tukiainen, Taru; Tsang, Emily K; Rivas, Manuel A; Pirinen, Matti; Gutierrez-Arcelus, Maria; Smith, Kevin S; Kukurba, Kim R; Zhang, Rui; Eng, Celeste; Torgerson, Dara G; Urbanek, Cydney; Li, Jin Billy; Rodriguez-Santana, Jose R; Burchard, Esteban G; Seibold, Max A; MacArthur, Daniel G; Montgomery, Stephen B; Zaitlen, Noah A; Lappalainen, Tuuli

    2015-07-01

    Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues. PMID:25953952

  12. The landscape of genomic imprinting across diverse adult human tissues

    PubMed Central

    Baran, Yael; Subramaniam, Meena; Biton, Anne; Tukiainen, Taru; Tsang, Emily K.; Rivas, Manuel A.; Pirinen, Matti; Gutierrez-Arcelus, Maria; Smith, Kevin S.; Kukurba, Kim R.; Zhang, Rui; Eng, Celeste; Torgerson, Dara G.; Urbanek, Cydney; Li, Jin Billy; Rodriguez-Santana, Jose R.; Burchard, Esteban G.; Seibold, Max A.; MacArthur, Daniel G.; Montgomery, Stephen B.; Zaitlen, Noah A.; Lappalainen, Tuuli

    2015-01-01

    Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues. PMID:25953952

  13. ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes.

    PubMed

    Voon, Hsiao P J; Hughes, Jim R; Rode, Christina; De La Rosa-Velázquez, Inti A; Jenuwein, Thomas; Feil, Robert; Higgs, Douglas R; Gibbons, Richard J

    2015-04-21

    Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. H3.3 deposition at euchromatin is dependent on HIRA, whereas ATRX/Daxx deposits H3.3 at pericentric heterochromatin and telomeres. The role of H3.3 at heterochromatic regions is unknown, but mutations in the ATRX/Daxx/H3.3 pathway are linked to aberrant telomere lengthening in certain cancers. In this study, we show that ATRX-dependent deposition of H3.3 is not limited to pericentric heterochromatin and telomeres but also occurs at heterochromatic sites throughout the genome. Notably, ATRX/H3.3 specifically localizes to silenced imprinted alleles in mouse ESCs. ATRX KO cells failed to deposit H3.3 at these sites, leading to loss of the H3K9me3 heterochromatin modification, loss of repression, and aberrant allelic expression. We propose a model whereby ATRX-dependent deposition of H3.3 into heterochromatin is normally required to maintain the memory of silencing at imprinted loci. PMID:25865896

  14. Imprinted Zac1 in neural stem cells

    PubMed Central

    Daniel, Guillaume; Schmidt-Edelkraut, Udo; Spengler, Dietmar; Hoffmann, Anke

    2015-01-01

    Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging. PMID:25815116

  15. DNA sequence polymorphisms in a panel of eight candidate bovine imprinted genes and their association with performance traits in Irish Holstein-Friesian cattle

    PubMed Central

    2010-01-01

    Background Studies in mice and humans have shown that imprinted genes, whereby expression from one of the two parentally inherited alleles is attenuated or completely silenced, have a major effect on mammalian growth, metabolism and physiology. More recently, investigations in livestock species indicate that genes subject to this type of epigenetic regulation contribute to, or are associated with, several performance traits, most notably muscle mass and fat deposition. In the present study, a candidate gene approach was adopted to assess 17 validated single nucleotide polymorphisms (SNPs) and their association with a range of performance traits in 848 progeny-tested Irish Holstein-Friesian artificial insemination sires. These SNPs are located proximal to, or within, the bovine orthologs of eight genes (CALCR, GRB10, PEG3, PHLDA2, RASGRF1, TSPAN32, ZIM2 and ZNF215) that have been shown to be imprinted in cattle or in at least one other mammalian species (i.e. human/mouse/pig/sheep). Results Heterozygosities for all SNPs analysed ranged from 0.09 to 0.46 and significant deviations from Hardy-Weinberg proportions (P ≤ 0.01) were observed at four loci. Phenotypic associations (P ≤ 0.05) were observed between nine SNPs proximal to, or within, six of the eight analysed genes and a number of performance traits evaluated, including milk protein percentage, somatic cell count, culled cow and progeny carcass weight, angularity, body conditioning score, progeny carcass conformation, body depth, rump angle, rump width, animal stature, calving difficulty, gestation length and calf perinatal mortality. Notably, SNPs within the imprinted paternally expressed gene 3 (PEG3) gene cluster were associated (P ≤ 0.05) with calving, calf performance and fertility traits, while a single SNP in the zinc finger protein 215 gene (ZNF215) was associated with milk protein percentage (P ≤ 0.05), progeny carcass weight (P ≤ 0.05), culled cow carcass weight (P ≤ 0.01), angularity (P

  16. Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.

    PubMed Central

    Baysal, B E; Farr, J E; Rubinstein, W S; Galus, R A; Johnson, K A; Aston, C E; Myers, E N; Johnson, J T; Carrau, R; Kirkpatrick, S J; Myssiorek, D; Singh, D; Saha, S; Gollin, S M; Evans, G A; James, M R; Richard, C W

    1997-01-01

    Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 168000) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subject to genomic imprinting. Genetic linkage analysis in two large, unrelated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 North American PGL families and confirmed maternal imprinting (inactivation). In three of six families, linkage analysis provided evidence of linkage to the PGL1 locus at 11q23. Recombinants narrowed the critical region to an approximately 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of symptoms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onset of symptoms in 39 of 57 father-child pairs (chi2 = 7.74, P < .006). However, a more conservative comparison of the number of pairs in which a child had > or = 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no significant difference (chi2 = 1.42, P > .2). Whether these data represent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs. PMID:8981955

  17. Deletion of the miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 locus enhances anxiety-related behaviour.

    PubMed

    Marty, Virginie; Labialle, Stéphane; Bortolin-Cavaillé, Marie-Line; Ferreira De Medeiros, Gabriela; Moisan, Marie-Pierre; Florian, Cédrick; Cavaillé, Jérôme

    2016-02-15

    The brain-specific miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 domain is implicated in several aspects of brain development and function, particularly in fine-tuning the dendritic outgrowth and spine remodelling of hippocampal neurons. Whether it might influence behaviour and memory-related processes has not yet been explored at the whole organism level. We previously reported that constitutive deletion of the miR-379/miR-410 gene cluster affects metabolic adaptation in neonatal mice. Here, we examined the role of this cluster in adult brain functions by subjecting mice with the constitutive deletion to a battery of behavioural and cognitive tests. We found that the lack of miR-379/miR-410 expression is associated with abnormal emotional responses, as demonstrated by increased anxiety-related behaviour in unfamiliar environments. In contrast, spontaneous exploration, general locomotion, mood levels and sociability remained unaltered. Surprisingly, miR-379/miR-410-deficient mice also showed normal learning and spatial (or contextual) memory abilities in hippocampus-dependent tasks involving neuronal plasticity. Taken together, the imprinted miR-379/miR-410 gene cluster thus emerges as a novel regulator of the two main post-natal physiological processes previously associated with imprinted, protein-coding genes: behaviour and energy homeostasis. PMID:26744330

  18. In vitro culture and somatic cell nuclear transfer affect imprinting of SNRPN gene in pre- and post-implantation stages of development in cattle

    PubMed Central

    Suzuki, Joao; Therrien, Jacinthe; Filion, France; Lefebvre, Rejean; Goff, Alan K; Smith, Lawrence C

    2009-01-01

    Background Embryo in vitro manipulations during early development are thought to increase mortality by altering the epigenetic regulation of some imprinted genes. Using a bovine interspecies model with a single nucleotide polymorphism, we assessed the imprinting status of the small nuclear ribonucleoprotein polypeptide N (SNRPN) gene in bovine embryos produced by artificial insemination (AI), in vitro culture (IVF) and somatic cell nuclear transfer (SCNT) and correlated allelic expression with the DNA methylation patterns of a differentially methylated region (DMR) located on the SNRPN promoter. Results In the AI group, SNRPN maternal expression is silenced at day 17 and 40 of development and a third of the alleles analyzed are methylated in the DMR. In the IVF group, maternal transcripts were identified at day 17 but methylation levels were similar to the AI group. However, day-40 fetuses in the IVF group showed significantly less methylation when compared to the AI group and SNRPN expression was mostly paternal in all fetal tissues studied, except in placenta. Finally, the SCNT group presented severe loss of DMR methylation in both day-17 embryos and 40 fetuses and biallelic expression was observed in all stages and tissues analyzed. Conclusion Together these results suggest that artificial reproductive techniques, such as prolonged in vitro culture and SCNT, lead to abnormal reprogramming of imprinting of SNRPN gene by altering methylation levels at this locus. PMID:19200381

  19. In Vitro Culture Increases the Frequency of Stochastic Epigenetic Errors at Imprinted Genes in Placental Tissues from Mouse Concepti Produced Through Assisted Reproductive Technologies1

    PubMed Central

    de Waal, Eric; Mak, Winifred; Calhoun, Sondra; Stein, Paula; Ord, Teri; Krapp, Christopher; Coutifaris, Christos; Schultz, Richard M.; Bartolomei, Marisa S.

    2014-01-01

    ABSTRACT Assisted reproductive technologies (ART) have enabled millions of couples with compromised fertility to conceive children. Nevertheless, there is a growing concern regarding the safety of these procedures due to an increased incidence of imprinting disorders, premature birth, and low birth weight in ART-conceived offspring. An integral aspect of ART is the oxygen concentration used during in vitro development of mammalian embryos, which is typically either atmospheric (∼20%) or reduced (5%). Both oxygen tension levels have been widely used, but 5% oxygen improves preimplantation development in several mammalian species, including that of humans. To determine whether a high oxygen tension increases the frequency of epigenetic abnormalities in mouse embryos subjected to ART, we measured DNA methylation and expression of several imprinted genes in both embryonic and placental tissues from concepti generated by in vitro fertilization (IVF) and exposed to 5% or 20% oxygen during culture. We found that placentae from IVF embryos exhibit an increased frequency of abnormal methylation and expression profiles of several imprinted genes, compared to embryonic tissues. Moreover, IVF-derived placentae exhibit a variety of epigenetic profiles at the assayed imprinted genes, suggesting that these epigenetic defects arise by a stochastic process. Although culturing embryos in both of the oxygen concentrations resulted in a significant increase of epigenetic defects in placental tissues compared to naturally conceived controls, we did not detect significant differences between embryos cultured in 5% and those cultured in 20% oxygen. Thus, further optimization of ART should be considered to minimize the occurrence of epigenetic errors in the placenta. PMID:24337315

  20. A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies.

    PubMed

    Sun, Jingnan; Li, Wei; Sun, Yunpeng; Yu, Dehai; Wen, Xue; Wang, Hong; Cui, Jiuwei; Wang, Guanjun; Hoffman, Andrew R; Hu, Ji-Fan

    2014-09-01

    Dysregulation of the insulin-like growth factor type I receptor (IGF1R) has been implicated in the progression and therapeutic resistance of malignancies. In acute myeloid leukemia (AML) cells, IGF1R is one of the most abundantly phosphorylated receptor tyrosine kinases, promoting cell growth through the PI3K/Akt signaling pathway. However, little is known regarding the molecular mechanisms underlying IGF1R gene dysregulation in cancer. We discovered a novel intragenic long noncoding RNA (lncRNA) within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter. The IRAIN lncRNA was expressed exclusively from the paternal allele, with the maternal counterpart being silenced. Using both reverse transcription-associated trap and chromatin conformation capture assays, we demonstrate that this lncRNA interacts with chromatin DNA and is involved in the formation of an intrachromosomal enhancer/promoter loop. Knockdown of IRAIN lncRNA with shRNA abolishes this intrachromosomal interaction. In addition, IRAIN was downregulated both in leukemia cell lines and in blood obtained from high-risk AML patients. These data identify IRAIN as a new imprinted lncRNA that is involved in long-range DNA interactions. PMID:25092925

  1. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene.

    PubMed

    Mantovani, Giovanna; Maghnie, Mohamad; Weber, Giovanna; De Menis, Ernesto; Brunelli, Valeria; Cappa, Marco; Loli, Paola; Beck-Peccoz, Paolo; Spada, Anna

    2003-09-01

    Heterozygous inactivating mutations in the Gs alpha gene cause Albright's hereditary osteodystrophy. Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action [pseudohypoparathyroidism type Ia (PHP Ia)], recent studies provided evidence for a predominant maternal origin of Gs alpha transcripts in endocrine organs, such as thyroid, gonad, and pituitary. The aim of this study was to investigate the presence of pituitary resistance to hypothalamic hormones acting via Gs alpha-coupled receptors in patients with PHP Ia. Six of nine patients showed an impaired GH responsiveness to GHRH plus arginine, consistent with a complete GH deficiency (GH peak from 2.6-8.6 microg/liter, normal > 16.5), and partial (GH peak 13.9 and 13.6 microg/liter) and normal responses were found in two and one patient, respectively. Accordingly, IGF-I levels were below and in the low-normal range in seven and two patients. All patients had a normal cortisol response to 1 microg ACTH test, suggesting a normal corticotroph function that was confirmed by a normal ACTH and cortisol response to CRH test in three patients. In conclusion, we report that in addition to PTH and TSH resistance, patients with PHP Ia display variable degrees of GHRH resistance, consistent with Gs alpha imprinting in human pituitary. PMID:12970263

  2. Genomic imprinting: mechanism and role in human pathology.

    PubMed Central

    Tycko, B.

    1994-01-01

    Most genes are expressed from two alleles, one maternal and the other paternal. The term "genomic imprinting" refers to a genetic phenomenon which produces some interesting exceptions to this rule. Genes which are subject to imprinting are molecularly marked before fertilization such that they are transcriptionally silenced at one of the parental alleles in the offspring. A growing body of evidence implicates genomic imprinting in the pathogenesis of certain human genetic diseases, inherited tumor syndromes, and sporadic tumors. This review discusses examples of imprinting, theories as to why the phenomenon exists, possible molecular mechanisms of imprinting, and our current understanding of the role of imprinting in human pathology. PMID:8129028

  3. Detection of transcriptional difference of porcine imprinted genes using different microarray platforms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Presently, multiple options exist for conducting gene expression profiling studies in swine. In order to determine the performance of some of the existing platforms, Affymetrix Porcine, Affymetrix Human U133+2.0, and the U.S. Pig Genome Coordination Program spotted glass oligonucleotide microarray p...

  4. Maternal low protein diet and postnatal high fat diet increases adipose imprinted gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maternal and postnatal diet can alter Igf2 gene expression and DNA methylation. To test whether maternal low protein and postnatal high fat (HF) diet result in alteration in Igf2 expression and obesity, we fed obese-prone Sprague-Dawley rats 8% (LP) or 20% (NP) protein for 3 wk prior to breeding and...

  5. Post-natal imprinting: evidence from marsupials.

    PubMed

    Stringer, J M; Pask, A J; Shaw, G; Renfree, M B

    2014-08-01

    Genomic imprinting has been identified in therian (eutherian and marsupial) mammals but not in prototherian (monotreme) mammals. Imprinting has an important role in optimising pre-natal nutrition and growth, and most imprinted genes are expressed and imprinted in the placenta and developing fetus. In marsupials, however, the placental attachment is short-lived, and most growth and development occurs post-natally, supported by a changing milk composition tailor-made for each stage of development. Therefore there is a much greater demand on marsupial females during post-natal lactation than during pre-natal placentation, so there may be greater selection for genomic imprinting in the mammary gland than in the short-lived placenta. Recent studies in the tammar wallaby confirm the presence of genomic imprinting in nutrient-regulatory genes in the adult mammary gland. This suggests that imprinting may influence infant post-natal growth via the mammary gland as it does pre-natally via the placenta. Similarly, an increasing number of imprinted genes have been implicated in regulating feeding and nurturing behaviour in both the adult and the developing neonate/offspring in mice. Together these studies provide evidence that genomic imprinting is critical for regulating growth and subsequently the survival of offspring not only pre-natally but also post-natally. PMID:24595366

  6. The male transmission bias of the insulin (INS) gene in insulin-dependent diabetes (IDD) can not be explained by maternal imprinting

    SciTech Connect

    Bui, M.M.; She, J.X.

    1994-09-01

    A locus contributing to IDD susceptibility has previously been mapped to a region on human chromosome 11p near the INS gene. To fine map the position of this susceptibility locus, polymorphisms in and flanking INS were analyzed in normal and IDD populations by PCR and restriction enzyme digestion. Regions flanking INS were not associated with IDD (p=NS). In contrast, homozygosity for the {open_quotes}+{close_quotes} INS allele was significantly increased in the IDD population (n=197) compared to 159 controls (RR=2.0, p<0.005), indicating an INS association with IDD. Transmission of the IDD-associated INS {open_quotes}+{close_quotes} alleles from parents to children in unaffected families was random (p=NS). However, in 107 multiplex and 15 simplex IDD families, transmission of the INS {open_quotes}+{close_quotes} allele from heterozygous parents to diabetic children revealed linkage of the INS gene to IDD (p<0.003). This linkage was limited to male meioses (p=0.01), suggest the potential for maternal imprinting of INS. The expression of the {open_quotes}+{close_quotes} and {open_quotes}-{close_quotes} INS allele was analyzed by RT-PCR in two normal heterozygous human fetal pancreases. Both transcripts were detected, indicating a lack of INS maternal imprinting in the human pancreas. Our results suggest that the IDD susceptibility locus on 11p is the INS gene, and that male transmission bias of the INS gene in IDD can not be explained by maternal imprinting.

  7. Identification of transgenic cloned dairy goats harboring human lactoferrin and methylation status of the imprinted gene IGF2R in their lungs.

    PubMed

    Zhang, Y L; Zhang, G M; Wan, Y J; Jia, R X; Li, P Z; Han, L; Wang, F; Huang, M R

    2015-01-01

    Dairy goat is a good model for production of transgenic proteins in milk using somatic cell nuclear transfer (SCNT). However, animals produced from SCNT are often associated with lung deficiencies. We recently produced six transgenic cloned dairy goats harboring the human lactoferrin gene, including three live transgenic clones and three deceased transgenic clones that died from respiratory failure during the perinatal period. Imprinted genes are important regulators of lung growth, and may be subjected to faulty reprogramming. In the present study, first, microsatellite analysis, PCR, and DNA sequence identification were conducted to confirm that these three dead kids were genetically identical to the transgenic donor cells. Second, the CpG island methylation profile of the imprinted insulin-like growth factor receptor (IGF2R) gene was assessed in the lungs of the three dead transgenic kids and the normally produced kids using bisulfite sequencing PCR. In addition, the relative mRNA level of IGF2R was also determined by real-time PCR. Results showed that the IGF2R gene in the lungs of the dead cloned kids showed abnormal hypermethylation and higher mRNA expression levels than the control, indicating that aberrant DNA methylation reprogramming is one of the important factors in the death of transgenic cloned animals. PMID:26400340

  8. Epigenetic Mechanisms of Genomic Imprinting: Common Themes in the Regulation of Imprinted Regions in Mammals, Plants, and Insects

    PubMed Central

    MacDonald, William A.

    2012-01-01

    Genomic imprinting is a form of epigenetic inheritance whereby the regulation of a gene or chromosomal region is dependent on the sex of the transmitting parent. During gametogenesis, imprinted regions of DNA are differentially marked in accordance to the sex of the parent, resulting in parent-specific expression. While mice are the primary research model used to study genomic imprinting, imprinted regions have been described in a broad variety of organisms, including other mammals, plants, and insects. Each of these organisms employs multiple, interrelated, epigenetic mechanisms to maintain parent-specific expression. While imprinted genes and imprint control regions are often species and locus-specific, the same suites of epigenetic mechanisms are often used to achieve imprinted expression. This review examines some examples of the epigenetic mechanisms responsible for genomic imprinting in mammals, plants, and insects. PMID:22567394

  9. Pyrosequencing for Accurate Imprinted Allele Expression Analysis

    PubMed Central

    Yang, Bing; Damaschke, Nathan; Yao, Tianyu; McCormick, Johnathon; Wagner, Jennifer; Jarrard, David

    2016-01-01

    Genomic imprinting is an epigenetic mechanism that restricts gene expression to one inherited allele. Improper maintenance of imprinting has been implicated in a number of human diseases and developmental syndromes. Assays are needed that can quantify the contribution of each paternal allele to a gene expression profile. We have developed a rapid, sensitive quantitative assay for the measurement of individual allelic ratios termed Pyrosequencing for Imprinted Expression (PIE). Advantages of PIE over other approaches include shorter experimental time, decreased labor, avoiding the need for restriction endonuclease enzymes at polymorphic sites, and prevent heteroduplex formation which is problematic in quantitative PCR-based methods. We demonstrate the improved sensitivity of PIE including the ability to detect differences in allelic expression down to 1%. The assay is capable of measuring genomic heterozygosity as well as imprinting in a single run. PIE is applied to determine the status of Insulin-like Growth Factor-2 (IGF2) imprinting in human and mouse tissues. PMID:25581900

  10. Genomic imprinting effects on complex traits in domesticated animal species

    PubMed Central

    O’Doherty, Alan M.; MacHugh, David E.; Spillane, Charles; Magee, David A.

    2015-01-01

    Monoallelically expressed genes that exert their phenotypic effect in a parent-of-origin specific manner are considered to be subject to genomic imprinting, the most well understood form of epigenetic regulation of gene expression in mammals. The observed differences in allele specific gene expression for imprinted genes are not attributable to differences in DNA sequence information, but to specific chemical modifications of DNA and chromatin proteins. Since the discovery of genomic imprinting some three decades ago, over 100 imprinted mammalian genes have been identified and considerable advances have been made in uncovering the molecular mechanisms regulating imprinted gene expression. While most genomic imprinting studies have focused on mouse models and human biomedical disorders, recent work has highlighted the contributions of imprinted genes to complex trait variation in domestic livestock species. Consequently, greater understanding of genomic imprinting and its effect on agriculturally important traits is predicted to have major implications for the future of animal breeding and husbandry. In this review, we discuss genomic imprinting in mammals with particular emphasis on domestic livestock species and consider how this information can be used in animal breeding research and genetic improvement programs. PMID:25964798

  11. Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development

    PubMed Central

    Koppes, Erik; Himes, Katherine P.; Chaillet, J. Richard

    2015-01-01

    Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte–derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function. PMID:26241757

  12. Genetic conflicts, multiple paternity and the evolution of genomic imprinting.

    PubMed Central

    Spencer, H G; Feldman, M W; Clark, A G

    1998-01-01

    We present nine diallelic models of genetic conflict in which one allele is imprintable and the other is not to examine how genomic imprinting may have evolved. Imprinting is presumed to be either maternal (i.e., the maternally derived gene is inactivated) or paternal. Females are assumed to be either completely monogamous or always bigamous, so that we may see any effect of multiple paternity. In contrast to previous verbal and quantitative genetic models, we find that genetic conflicts need not lead to paternal imprinting of growth inhibitors and maternal imprinting of growth enhancers. Indeed, in some of our models--those with strict monogamy--the dynamics of maternal and paternal imprinting are identical. Multiple paternity is not necessary for the evolution of imprinting, and in our models of maternal imprinting, multiple paternity has no effect at all. Nevertheless, multiple paternity favors the evolution of paternal imprinting of growth inhibitors and hinders that of growth enhancers. Hence, any degree of multiple paternity means that growth inhibitors are more likely to be paternally imprinted, and growth enhancers maternally so. In all of our models, stable polymorphism of imprinting status is possible and mean fitness can decrease over time. Neither of these behaviors have been predicted by previous models. PMID:9504935

  13. Inactive allele-specific methylation and chromatin structure of the imprinted gene U2af1-rs1 on mouse chromosome 11

    SciTech Connect

    Shibata, Hideo; Yoshino, Kiyoshi; Kamiya, Mamoru

    1996-07-01

    The imprinted U2Af1-rs1 gene that maps to mouse chromosome 11 is predominately expressed from the paternal allele. We examined the methylation of genomic sequences in and around the U2af1-rs1 locus to establish the extent of sequence modifications that accompanied the silencing of the maternal allele. The analysis of HapII or HhaI sites showed that the silent maternal allele was hypermethylated in a block of CpG sequences that covered more than 10 kb. By comparison, the expressed paternal allele was unmethylated from a CpG island upstream of the transcribed region through 2 kb. An analysis of DNaseI hypersensitivity of a putative promoter of U2af1-rs1 showed an open chromatin conformation only on the unmethylated, expressed paternal allele. These results suggest that allele-specific hypermethylation covering the gene and its upstream CpG island plays a role in maternal allele repression of U2af1-rs1, which is reflected in altered chromatin conformation of DNaseI hypersensitive sites. 9 refs., 2 figs.

  14. Effect of BIX-01294 on H3K9me2 levels and the imprinted gene Snrpn in mouse embryonic fibroblast cells

    PubMed Central

    Chen, Peng; Yao, Jian-Feng; Huang, Rong-Fu; Zheng, Fang-Fang; Jiang, Xiao-Hong; Chen, Xuan; Chen, Juan; Li, Ming; Huang, Hong-Feng; Jiang, Yi-Ping; Huang, Yan-Fang; Yang, Xiao-Yu

    2015-01-01

    Histone H3 lysine 9 dimethylation (H3K9me2) hypermethylation is thought to be a major influential factor in cellular reprogramming, such as somatic cell nuclear transfer (SCNT) and induction of pluripotent stem cells (iPSCs). The diazepin-quinazolin-amine derivative (BIX-01294) specifically inhibits the activity of histone methyltransferase EHMT2 (euchromatic histone-lysine N-methyltransferase 2) and reduces H3K9me2 levels in cells. The imprinted gene small nuclear ribonucleoprotein N (Snrpn) is of particular interest because of its important biological functions. The objective of the present study was to investigate the effect of BIX-01294 on H3K9me2 levels and changes in Snrpn DNA methylation and histone H3K9me2 in mouse embryonic fibroblasts (MEFs). Results showed that 1.3 μM BIX-01294 markedly reduced global levels of H3K9me2 with almost no cellular toxicity. There was a significant decrease in H3K9me2 in promoter regions of the Snrpn gene after BIX-01294 treatment. A significant increase in methylation of the Snrpn differentially methylated region 1 (DMR1) and slightly decreased transcript levels of Snrpn were found in BIX-01294-treated MEFs. These results suggest that BIX-01294 may reduce global levels of H3K9me2 and affect epigenetic modifications of Snrpn in MEFs. PMID:26285804

  15. Loss of imprinting of the insulin-like growth factor II gene in mouse hepatocellular carcinoma cell lines.

    PubMed

    Ooasa, T; Karasaki, H; Kanda, H; Nomura, K; Kitagawa, T; Ogawa, K

    1998-12-01

    We investigated expression of insulin-like growth factor II (Igf2) in primary cultured hepatocytes, liver epithelial (LE) cell lines derived from normal hepatocytes, and hepatocellular carcinoma (HCC) cell lines from crosses between C3H/HeJ (C3H) and Mus musculus molossinus mice (MSM). Igf2 mRNA was detected by reverse transcriptase-polymerase chain reaction in primary cultured hepatocytes from 5 d after the start of cultivation and in all 12 LE and 16 HCC cell lines. Analysis of the untranslated region of Igf2 exon 6, which contains polymorphic CA repeats, revealed that 13 of the 16 HCC cell lines had biallelic expression, whereas monoallelic expression was retained in the primary cultured hepatocytes and all 12 LE cell lines. The Igf2 transcripts contained exons 1-3 in all the HCC cell lines but only exons 2 and 3 in cultures of hepatocytes and LE cell lines, indicating difference in promoter use. However, the biallelic HCC cell lines did not have larger amounts of Igf2 mRNA and protein than did the monoallelic lines, suggesting that loss of imprinting may not be directly related to the level of Igf2 expression. PMID:9869454

  16. Genomic imprinting is disrupted in interspecific Peromyscus hybrids.

    PubMed

    Vrana, P B; Guan, X J; Ingram, R S; Tilghman, S M

    1998-12-01

    Genomic imprinting, the unequal expression of gene alleles on the basis of parent of origin, is a major exception to mendelian laws of inheritance. By maintaining one allele of a gene in a silent state, imprinted genes discard the advantages of diploidy, and for this reason the rationale for the evolution of imprinting has been debated. One explanation is the parent-offspring conflict model, which proposes that imprinting arose in polyandrous mammals as the result of a parental conflict over the allocation of maternal resources to embryos. This theory predicts that there should be no selection for imprinting in a monogamous species. Crosses between the monogamous rodent species Peromyscus polionotus and the polyandrous Peromyscus maniculatus yield progeny with parent-of-origin growth defects that could be explained if imprinting was absent in the monogamous species. We find, however, that imprinting is maintained in P. polionotus, but there is widespread disruption of imprinting in the hybrids. We suggest that the signals governing genomic imprinting are rapidly evolving and that disruptions in the process may contribute to mammalian speciation. PMID:9843208

  17. Imprinting in plants as a mechanism to generate seed phenotypic diversity

    PubMed Central

    Bai, Fang; Settles, A. M.

    2015-01-01

    Normal plant development requires epigenetic regulation to enforce changes in developmental fate. Genomic imprinting is a type of epigenetic regulation in which identical alleles of genes are expressed in a parent-of-origin dependent manner. Deep sequencing of transcriptomes has identified hundreds of imprinted genes with scarce evidence for the developmental importance of individual imprinted loci. Imprinting is regulated through global DNA demethylation in the central cell prior to fertilization and directed repression of individual loci with the Polycomb Repressive Complex 2 (PRC2). There is significant evidence for transposable elements and repeat sequences near genes acting as cis-elements to determine imprinting status of a gene, implying that imprinted gene expression patterns may evolve randomly and at high frequency. Detailed genetic analysis of a few imprinted loci suggests an imprinted pattern of gene expression is often dispensable for seed development. Few genes show conserved imprinted expression within or between plant species. These data are not fully explained by current models for the evolution of imprinting in plant seeds. We suggest that imprinting may have evolved to provide a mechanism for rapid neofunctionalization of genes during seed development to increase phenotypic diversity of seeds. PMID:25674092

  18. Genomic imprinting and position-effect variegation in Drosophila melanogaster.

    PubMed Central

    Lloyd, V K; Sinclair, D A; Grigliatti, T A

    1999-01-01

    Genomic imprinting is a phenomenon in which the expression of a gene or chromosomal region depends on the sex of the individual transmitting it. The term imprinting was first coined to describe parent-specific chromosome behavior in the dipteran insect Sciara and has since been described in many organisms, including other insects, plants, fish, and mammals. In this article we describe a mini-X chromosome in Drosophila melanogaster that shows genomic imprinting of at least three closely linked genes. The imprinting of these genes is observed as mosaic silencing when the genes are transmitted by the male parent, in contrast to essentially wild-type expression when the same genes are maternally transmitted. We show that the imprint is due to the sex of the parent rather than to a conventional maternal effect, differential mitotic instability of the mini-X chromosome, or an allele-specific effect. Finally, we have examined the effects of classical modifiers of position-effect variegation on the maintenance and the establishment of the imprint. Factors that modify position-effect variegation alter the somatic expression but not the establishment of the imprint. This suggests that chromatin structure is important in maintenance of the imprint, but a separate mechanism may be responsible for its initiation. PMID:10101173

  19. Maternal and paternal genomes function independently in mouse ova in establishing expression of the imprinted genes Snrpn and Igf2r: no evidence for allelic trans-sensing and counting mechanisms.

    PubMed Central

    Szabó, P E; Mann, J R

    1996-01-01

    It has often been suggested that the parental-specific expression of mammalian imprinted genes might be dependent on maternal-paternal intergenomic or interallelic interactions. Using quantitative allele-specific RT-PCR single nucleotide primer extension assays developed for two imprinted genes, Snrpn and Igf2r, we demonstrate: (i) No role for maternal-paternal allelic interactions: the modes of parental-specific expression of Snrpn and Igf2r in normal ova were unchanged in gynogenetic and androgenetic ova; the latter contain two maternal and two paternal genomes respectively, and cannot undergo maternal-paternal interactions. (ii) No role for allelic counting or exclusion mechanisms: in individual blastomeres of androgenetic ova, both paternal Snrpn alleles were active (Snrpn was not expressed in gynogenetic ova), and in individual gynogenetic and androgenetic blastomeres, both maternal and paternal Igf2r alleles, respectively, were active. (iii) No role for ploidy: the mode of parental-specific expression of Snrpn and Igf2r in normal diploid ova was unchanged in individual blastomeres of triploid and tetraploid ova. Thus, the maternal and paternal genomes function independently in establishing the pre-implantation mode of parental-specific expression of Snrpn and Igf2r, with no role for trans-allelic/genomic interaction phenomena. In addition, the results show that inactive and biallelic modes of expression of imprinted genes are potential mechanisms for the death of gynogenones and androgenones at the peri-implantation stage. Images PMID:8947024

  20. Epigenetic status of H19/IGF2 and SNRPN imprinted genes in aborted and successfully derived embryonic stem cell lines in non-human primates.

    PubMed

    Wianny, Florence; Blachère, Thierry; Godet, Murielle; Guillermas, Rémi; Cortay, Véronique; Bourillot, Pierre-Yves; Lefèvre, Annick; Savatier, Pierre; Dehay, Colette

    2016-05-01

    The imprinted genes of primate embryonic stem cells (ESCs) often show altered DNA methylation. It is unknown whether these alterations emerge while deriving the ESCs. Here we studied the methylation patterns of two differentially methylated regions (DMRs), SNRPN and H19/IGF2 DMRs, during the derivation of monkey ESCs. We show that the SNRPN DMR is characteristically methylated at maternal alleles, whereas the H19/IGF2 DMR is globally highly methylated, with unusual methylation on the maternal alleles. These methylation patterns remain stable from the early stages of ESC derivation to late passages of monkey ESCs and following differentiation. Importantly, the methylation status of H19/IGF2 DMR and the expression levels of IGF2, H19, and DNMT3B mRNAs in early embryo-derived cells were correlated with their capacity to generate genuine ESC lines. Thus, we propose that these markers could be useful to predict the outcomes of establishing an ESC line in primates. PMID:26999759

  1. Applicability of the parentally imprinted allele (PIA) typing of a VNTR upstream the H19 gene to forensic samples of different tissues.

    PubMed

    Sumi, Hirokazu; Naito, Emiko; Dewa, Koji; Fukuda, Masaaki; Xu, Hong-De; Yamanouchi, Haruo

    2005-05-01

    The parentally imprinted allele (PIA) typing that we have recently developed determines parental alleles at a VNTR locus in the differentially methylated region upstream of the human H19 gene. The usefulness of this typing was demonstrated by its application to blood samples in paternity cases. However, its applicability to other tissue DNA remains to be tested. DNA samples from fifteen different postmortem tissues such as cerebrum, skeletal muscle and skin were examined, all of which were obtained from three autopsy cases 2-11h after death. DNA was digested with a methylation-sensitive HhaI enzyme and diluted solutions of the digests were subjected to the first PCR amplification, providing amplification of only the paternal H19 methylated allele. Subsequent VNTR typing was carried out for the amplified products to determine which allele was of paternal origin. No tissue-dependent difference was observed and all the samples examined, though degraded, were successfully used for determining the paternal allele. These results substantiate the usefulness of PIA typing in forensic examinations. Its application to two identity cases, a burned male body and a male body with adipocere formation, was also shown. PMID:15847827

  2. Genomic imprinting in the human placenta.

    PubMed

    Monk, David

    2015-10-01

    With the launch of the National Institute of Child Health and Human Development/National Institutes of Health Human Placenta Project, the anticipation is that this often-overlooked organ will be the subject of much intense research. Compared with somatic tissues, the cells of the placenta have a unique epigenetic profile that dictates its transcription patterns, which when disturbed may be associated with adverse pregnancy outcomes. One major class of genes that is dependent on strict epigenetic regulation in the placenta is subject to genomic imprinting, the parent-of-origin-dependent monoallelic gene expression. This review discusses the differences in allelic expression and epigenetic profiles of imprinted genes that are identified between different species, which reflect the continuous evolutionary adaption of this form of epigenetic regulation. These observations divulge that placenta-specific imprinted gene that is reliant on repressive histone signatures in mice are unlikely to be imprinted in humans, whereas intense methylation profiling in humans has uncovered numerous maternally methylated regions that are restricted to the placenta that are not conserved in mice. Imprinting has been proposed to be a mechanism that regulates parental resource allocation and ultimately can influence fetal growth, with the placenta being the key in this process. Furthermore, I discuss the developmental dynamics of both classic and transient placenta-specific imprinting and examine the evidence for an involvement of these genes in intrauterine growth restriction and placenta-associated complications. Finally, I focus on examples of genes that are regulated aberrantly in complicated pregnancies, emphasizing their application as pregnancy-related disease biomarkers to aid the diagnosis of at-risk pregnancies early in gestation. PMID:26428495

  3. Extensive, clustered parental imprinting of protein-coding and noncoding RNAs in developing maize endosperm.

    PubMed

    Zhang, Mei; Zhao, Hainan; Xie, Shaojun; Chen, Jian; Xu, Yuanyuan; Wang, Keke; Zhao, Haiming; Guan, Haiying; Hu, Xiaojiao; Jiao, Yinping; Song, Weibin; Lai, Jinsheng

    2011-12-13

    Although genetic imprinting was discovered in maize 40 years ago, its exact extent in the triploid endosperm remains unknown. Here, we have analyzed global patterns of allelic gene expression in developing maize endosperms from reciprocal crosses between inbreds B73 and Mo17. We have defined an imprinted gene as one in which the relative expression of the maternal and paternal alleles differ at least fivefold in both hybrids of the reciprocal crosses. We found that at least 179 genes (1.6% of protein-coding genes) expressed in the endosperm are imprinted, with 68 of them showing maternal preferential expression and 111 paternal preferential expression. Additionally, 38 long noncoding RNAs were imprinted. The latter are transcribed in either sense or antisense orientation from intronic regions of normal protein-coding genes or from intergenic regions. Imprinted genes show a clear pattern of clustering around the genome, with a number of imprinted genes being adjacent to each other. Analysis of allele-specific methylation patterns of imprinted loci in the hybrid endosperm identified 21 differentially methylated regions (DMRs) of several hundred base pairs in length, corresponding to both imprinted genes and noncoding transcripts. All DMRs identified are uniformly hypomethylated in maternal alleles and hypermethylated in paternal alleles, regardless of the imprinting direction of their corresponding loci. Our study indicates highly extensive and complex regulation of genetic imprinting in maize endosperm, a mechanism that can potentially function in the balancing of the gene dosage of this triploid tissue. PMID:22114195

  4. Genomic imprinting: A missing piece of the Multiple Sclerosis puzzle?

    PubMed

    Ruhrmann, Sabrina; Stridh, Pernilla; Kular, Lara; Jagodic, Maja

    2015-10-01

    Evidence for parent-of-origin effects in complex diseases such as Multiple Sclerosis (MS) strongly suggests a role for epigenetic mechanisms in their pathogenesis. In this review, we describe the importance of accounting for parent-of-origin when identifying new risk variants for complex diseases and discuss how genomic imprinting, one of the best-characterized epigenetic mechanisms causing parent-of-origin effects, may impact etiology of complex diseases. While the role of imprinted genes in growth and development is well established, the contribution and molecular mechanisms underlying the impact of genomic imprinting in immune functions and inflammatory diseases are still largely unknown. Here we discuss emerging roles of imprinted genes in the regulation of inflammatory responses with a particular focus on the Dlk1 cluster that has been implicated in etiology of experimental MS-like disease and Type 1 Diabetes. Moreover, we speculate on the potential wider impact of imprinting via the action of imprinted microRNAs, which are abundantly present in the Dlk1 locus and predicted to fine-tune important immune functions. Finally, we reflect on how unrelated imprinted genes or imprinted genes together with non-imprinted genes can interact in so-called imprinted gene networks (IGN) and suggest that IGNs could partly explain observed parent-of-origin effects in complex diseases. Unveiling the mechanisms of parent-of-origin effects is therefore likely to teach us not only about the etiology of complex diseases but also about the unknown roles of this fascinating phenomenon underlying uneven genetic contribution from our parents. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID:26002250

  5. Retrotransposon silencing by DNA methylation can drive mammalian genomic imprinting.

    PubMed

    Suzuki, Shunsuke; Ono, Ryuichi; Narita, Takanori; Pask, Andrew J; Shaw, Geoffrey; Wang, Changshan; Kohda, Takashi; Alsop, Amber E; Marshall Graves, Jennifer A; Kohara, Yuji; Ishino, Fumitoshi; Renfree, Marilyn B; Kaneko-Ishino, Tomoko

    2007-04-13

    Among mammals, only eutherians and marsupials are viviparous and have genomic imprinting that leads to parent-of-origin-specific differential gene expression. We used comparative analysis to investigate the origin of genomic imprinting in mammals. PEG10 (paternally expressed 10) is a retrotransposon-derived imprinted gene that has an essential role for the formation of the placenta of the mouse. Here, we show that an orthologue of PEG10 exists in another therian mammal, the marsupial tammar wallaby (Macropus eugenii), but not in a prototherian mammal, the egg-laying platypus (Ornithorhynchus anatinus), suggesting its close relationship to the origin of placentation in therian mammals. We have discovered a hitherto missing link of the imprinting mechanism between eutherians and marsupials because tammar PEG10 is the first example of a differentially methylated region (DMR) associated with genomic imprinting in marsupials. Surprisingly, the marsupial DMR was strictly limited to the 5' region of PEG10, unlike the eutherian DMR, which covers the promoter regions of both PEG10 and the adjacent imprinted gene SGCE. These results not only demonstrate a common origin of the DMR-associated imprinting mechanism in therian mammals but provide the first demonstration that DMR-associated genomic imprinting in eutherians can originate from the repression of exogenous DNA sequences and/or retrotransposons by DNA methylation. PMID:17432937

  6. DOES NUTRITION DURING INFANCY AND EARLY CHILDHOOD CONTRIBUTE TO LATER OBESITY VIA METABOLIC IMPRINTING OF EPIGENETIC GENE REGULATORY MECHANISMS?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Individual differences in physiological and behavioral factors affecting body weight regulation may be determined not only by genes, but also by environmental influences during development. This article reviews briefly evidence from human epidemiologic and animal model studies that during infancy an...

  7. Monotreme IGF2 expression and ancestral origin of genomic imprinting.

    PubMed

    Killian, J K; Nolan, C M; Stewart, N; Munday, B L; Andersen, N A; Nicol, S; Jirtle, R L

    2001-08-15

    IGF2 (insulin-like growth factor 2) and M6P/IGF2R (mannose 6-phosphate/insulin-like growth factor 2 receptor) are imprinted in marsupials and eutherians but not in birds. These results along with the absence of M6P/IGF2R imprinting in the egg-laying monotremes indicate that the parental imprinting of fetal growth-regulatory genes may be unique to viviparous mammals. In this investigation, we have cloned IGF2 from two monotreme mammals, the platypus and echidna, to further investigate the origin of imprinting. We report herein that like M6P/IGF2R, IGF2 is not imprinted in monotremes. Thus, although IGF2 encodes for a highly conserved growth factor in chordates, it is only imprinted in therian mammals. These findings support a concurrent origin of IGF2 and M6P/IGF2R imprinting in the late Jurassic/early Cretaceous period. The absence of imprinting in monotremes, despite apparent interparental conflicts over maternal-offspring exchange, argues that a fortuitous congruency of genetic and epigenetic events may have limited the phylogenetic breadth of genomic imprinting to therian mammals. J. Exp. Zool. (Mol. Dev. Evol.) 291:205-212, 2001. PMID:11479919

  8. The Wellcome Prize Lecture. Genetic imprinting: the battle of the sexes rages on.

    PubMed

    Reik, W

    1996-03-01

    Genomic imprinting in mammals is an important genetic mechanism by which genes are expressed or repressed depending on which parent they have been inherited from. Some properties of the imprinting mechanism are already established; notably, some of the effects of imprinting on mammalian development can be explained by the phenotypic effects of a number of specific imprinted genes, which include major fetal growth factors. An evolutionary explanation of imprinting has also been suggested. Some of the molecular mechanisms of imprinting are known, and these include the modification of DNA and chromosomes in the form of DNA methylation and possibly heritable chromatin structures. Loss of imprinting or altered imprinting is implicated in a large number of genetic diseases and cancers. Many important issues remain to be resolved; these include the precise molecular mechanisms and, in particular, the nature of the primary imprints that are inherited from the parental gametes, and the genes that control the imprinting process. Isolation of the majority of imprinted genes and the elucidation of their phenotypic effects and physiology are major goals for the future. These studies will provide important insights into human genetics, and will connect evolutionary understanding with physiology, genetic disease and human behaviour. PMID:8845132

  9. Theory of genomic imprinting conflict in social insects

    PubMed Central

    Queller, David C

    2003-01-01

    Background Genomic imprinting refers to the differential expression of genes inherited from the mother and father (matrigenes and patrigenes). The kinship theory of genomic imprinting treats parent-specific gene expression as products of within-genome conflict. Specifically, matrigenes and patrigenes will be in conflict over treatment of relatives to which they are differently related. Haplodiploid females have many such relatives, and social insects have many contexts in which they affect relatives, so haplodiploid social insects are prime candidates for tests of the kinship theory of imprinting. Results Matrigenic and patrigenic relatednesses are derived for individuals affected in a variety of contexts, including queen competition, sex ratio, worker laying of male eggs and policing, colony fission, and adoption of new queens. Numerous predictions emerge for what contexts should elicit imprinting, which individuals and tissues will show it, and the direction of imprinting effects. The predictions often vary for different genetic structures (varying queen and mate number) and often contrast with predictions for diploids. Conclusion Because the contexts differ from the normal imprinting case, and because nothing is currently known about imprinting in social insects, these predictions can serve as a strong a priori test of the kinship theory of imprinting. If the predictions are correct, then social insects, which have long served as exemplars of cooperation between individuals, will also be shown to be extraordinary examples of competition within individual genomes. PMID:12871603

  10. Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation

    PubMed Central

    Cheong, Clara Y.; Chng, Keefe; Ng, Shilen; Chew, Siew Boom; Chan, Louiza; Ferguson-Smith, Anne C.

    2015-01-01

    Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease. PMID:25862382

  11. Genomic imprinting in the Arabidopsis embryo is partly regulated by PRC2.

    PubMed

    Raissig, Michael T; Bemer, Marian; Baroux, Célia; Grossniklaus, Ueli

    2013-01-01

    Genomic imprinting results in monoallelic gene expression in a parent-of-origin-dependent manner and is regulated by the differential epigenetic marking of the parental alleles. In plants, genomic imprinting has been primarily described for genes expressed in the endosperm, a tissue nourishing the developing embryo that does not contribute to the next generation. In Arabidopsis, the genes MEDEA (MEA) and PHERES1 (PHE1), which are imprinted in the endosperm, are also expressed in the embryo; whether their embryonic expression is regulated by imprinting or not, however, remains controversial. In contrast, the maternally expressed in embryo 1 (mee1) gene of maize is clearly imprinted in the embryo. We identified several imprinted candidate genes in an allele-specific transcriptome of hybrid Arabidopsis embryos and confirmed parent-of-origin-dependent, monoallelic expression for eleven maternally expressed genes (MEGs) and one paternally expressed gene (PEG) in the embryo, using allele-specific expression analyses and reporter gene assays. Genetic studies indicate that the Polycomb Repressive Complex 2 (PRC2) but not the DNA METHYLTRANSFERASE1 (MET1) is involved in regulating imprinted expression in the embryo. In the seedling, all embryonic MEGs and the PEG are expressed from both parents, suggesting that the imprint is erased during late embryogenesis or early vegetative development. Our finding that several genes are regulated by genomic imprinting in the Arabidopsis embryo clearly demonstrates that this epigenetic phenomenon is not a unique feature of the endosperm in both monocots and dicots. PMID:24339783

  12. Genomic Imprinting in the Arabidopsis Embryo Is Partly Regulated by PRC2

    PubMed Central

    Raissig, Michael T.; Bemer, Marian; Baroux, Célia; Grossniklaus, Ueli

    2013-01-01

    Genomic imprinting results in monoallelic gene expression in a parent-of-origin-dependent manner and is regulated by the differential epigenetic marking of the parental alleles. In plants, genomic imprinting has been primarily described for genes expressed in the endosperm, a tissue nourishing the developing embryo that does not contribute to the next generation. In Arabidopsis, the genes MEDEA (MEA) and PHERES1 (PHE1), which are imprinted in the endosperm, are also expressed in the embryo; whether their embryonic expression is regulated by imprinting or not, however, remains controversial. In contrast, the maternally expressed in embryo 1 (mee1) gene of maize is clearly imprinted in the embryo. We identified several imprinted candidate genes in an allele-specific transcriptome of hybrid Arabidopsis embryos and confirmed parent-of-origin-dependent, monoallelic expression for eleven maternally expressed genes (MEGs) and one paternally expressed gene (PEG) in the embryo, using allele-specific expression analyses and reporter gene assays. Genetic studies indicate that the Polycomb Repressive Complex 2 (PRC2) but not the DNA METHYLTRANSFERASE1 (MET1) is involved in regulating imprinted expression in the embryo. In the seedling, all embryonic MEGs and the PEG are expressed from both parents, suggesting that the imprint is erased during late embryogenesis or early vegetative development. Our finding that several genes are regulated by genomic imprinting in the Arabidopsis embryo clearly demonstrates that this epigenetic phenomenon is not a unique feature of the endosperm in both monocots and dicots. PMID:24339783

  13. Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci.

    PubMed

    Eggermann, Thomas; Perez de Nanclares, Guiomar; Maher, Eamonn R; Temple, I Karen; Tümer, Zeynep; Monk, David; Mackay, Deborah J G; Grønskov, Karen; Riccio, Andrea; Linglart, Agnès; Netchine, Irène

    2015-01-01

    Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however, it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and disease, but also support personalisation of diagnosis and management for individual patients and families. PMID:26583054

  14. Generation of Five Human Lactoferrin Transgenic Cloned Goats Using Fibroblast Cells and Their Methylation Status of Putative Differential Methylation Regions of IGF2R and H19 Imprinted Genes

    PubMed Central

    Sun, Yanyan; Zhang, Yanli; Wang, Ziyu; Song, Yang; Wang, Feng

    2013-01-01

    Background Somatic cell nuclear transfer (SCNT) is a promising technique to produce transgenic cloned mammalian, including transgenic goats which may produce Human Lactoferrin (hLF). However, success percentage of SCNT is low, because of gestational and neonatal failure of transgenic embryos. According to the studies on cattle and mice, DNA methylation of some imprinted genes, which plays a vital role in the reprogramming of embryo in NT maybe an underlying mechanism. Methodology/Principal Findings Fibroblast cells were derived from the ear of a two-month-old goat. The vector expressing hLF was constructed and transfected into fibroblasts. G418 selection, EGFP expression, PCR, and cell cycle distribution were applied sequentially to select transgenic cells clones. After NT and embryo transfer, five transgenic cloned goats were obtained from 240 cloned transgenic embryos. These transgenic goats were identified by 8 microsatellites genotyping and southern blot. Of the five transgenic goats, 3 were lived after birth, while 2 were dead during gestation. We compared differential methylation regions (DMR) pattern of two paternally imprinted genes (H19 and IGF2R) of the ear tissues from the lived transgenic goats, dead transgenic goats, and control goats from natural reproduction. Hyper-methylation pattern appeared in cloned aborted goats, while methylation status was relatively normal in cloned lived goats compared with normal goats. Conclusions/Significance In this study, we generated five hLF transgenic cloned goats by SCNT. This is the first time the DNA methylation of lived and dead transgenic cloned goats was compared. The results demonstrated that the methylation status of DMRs of H19 and IGF2R were different in lived and dead transgenic goats and therefore this may be potentially used to assess the reprogramming status of transgenic cloned goats. Understanding the pattern of gene imprinting may be useful to improve cloning techniques in future. PMID:24204972

  15. Genomic Imprinting and Epigenetic Control of Development

    PubMed Central

    Fedoriw, Andrew; Mugford, Joshua; Magnuson, Terry

    2012-01-01

    Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development. PMID:22687277

  16. Genomic imprinting and epigenetic control of development.

    PubMed

    Fedoriw, Andrew; Mugford, Joshua; Magnuson, Terry

    2012-07-01

    Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development. PMID:22687277

  17. GRB10 imprinting is eutherian mammal specific.

    PubMed

    Stringer, Jessica M; Suzuki, Shunsuke; Pask, Andrew J; Shaw, Geoff; Renfree, Marilyn B

    2012-12-01

    GRB10 is an imprinted gene differently expressed from two promoters in mouse and human. Mouse Grb10 is maternally expressed from the major promoter in most tissues and paternally expressed from the brain-specific promoter within specific regions of the fetal and adult central nervous system. Human GRB10 is biallelically expressed from the major promoter in most tissues except in the placental villus trophoblast where it is maternally expressed, whereas the brain-specific promoter is paternally expressed in the fetal brain. This study characterized the ortholog of GRB10 in a marsupial, the tammar wallaby (Macropus eugenii) to investigate the origin and evolution of imprinting at this locus. The protein coding exons and predicted amino acid sequence of tammar GRB10 were highly conserved with eutherian GRB10. The putative first exon, which is located in the orthologous region to the eutherian major promoter, was found in the tammar, but no exon was found in the downstream region corresponding to the eutherian brain-specific promoter, suggesting that marsupials only have a single promoter. Tammar GRB10 was widely expressed in various tissues including the brain but was not imprinted in any of the tissues examined. Thus, it is likely that GRB10 imprinting evolved in eutherians after the eutherian-marsupial divergence approximately 160 million years ago, subsequent to the acquisition of a brain-specific promoter, which resides within the imprinting control region in eutherians. PMID:22787282

  18. Long noncoding RNAs: Lessons from genomic imprinting.

    PubMed

    Kanduri, Chandrasekhar

    2016-01-01

    Genomic imprinting has been a great resource for studying transcriptional and post-transcriptional-based gene regulation by long noncoding RNAs (lncRNAs). In this article, I overview the functional role of intergenic lncRNAs (H19, IPW, and MEG3), antisense lncRNAs (Kcnq1ot1, Airn, Nespas, Ube3a-ATS), and enhancer lncRNAs (IG-DMR eRNAs) to understand the diverse mechanisms being employed by them in cis and/or trans to regulate the parent-of-origin-specific expression of target genes. Recent evidence suggests that some of the lncRNAs regulate imprinting by promoting intra-chromosomal higher-order chromatin compartmentalization, affecting replication timing and subnuclear positioning. Whereas others act via transcriptional occlusion or transcriptional collision-based mechanisms. By establishing genomic imprinting of target genes, the lncRNAs play a critical role in important biological functions, such as placental and embryonic growth, pluripotency maintenance, cell differentiation, and neural-related functions such as synaptic development and plasticity. An emerging consensus from the recent evidence is that the imprinted lncRNAs fine-tune gene expression of the protein-coding genes to maintain their dosage in cell. Hence, lncRNAs from imprinted clusters offer insights into their mode of action, and these mechanisms have been the basis for uncovering the mode of action of lncRNAs in several other biological contexts. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID:26004516

  19. The evolution of genomic imprinting: theories, predictions and empirical tests

    PubMed Central

    Patten, M M; Ross, L; Curley, J P; Queller, D C; Bonduriansky, R; Wolf, J B

    2014-01-01

    The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal–offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal–offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted. PMID:24755983

  20. The evolution of genomic imprinting: theories, predictions and empirical tests.

    PubMed

    Patten, M M; Ross, L; Curley, J P; Queller, D C; Bonduriansky, R; Wolf, J B

    2014-08-01

    The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal-offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal-offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted. PMID:24755983

  1. Pervasive polymorphic imprinted methylation in the human placenta.

    PubMed

    Hanna, Courtney W; Peñaherrera, Maria S; Saadeh, Heba; Andrews, Simon; McFadden, Deborah E; Kelsey, Gavin; Robinson, Wendy P

    2016-06-01

    The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental-specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation. PMID:26769960

  2. Pervasive polymorphic imprinted methylation in the human placenta

    PubMed Central

    Hanna, Courtney W.; Peñaherrera, Maria S.; Saadeh, Heba; Andrews, Simon; McFadden, Deborah E.; Kelsey, Gavin; Robinson, Wendy P.

    2016-01-01

    The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental-specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation. PMID:26769960

  3. Genomic imprinting, methylation and parent-of-origin effects in reciprocal hybrid endosperm of castor bean

    PubMed Central

    Xu, Wei; Dai, Mengyuan; Li, Fei; Liu, Aizhong

    2014-01-01

    Genomic imprinting often results in parent-of-origin specific differential expression of maternally and paternally inherited alleles. In plants, the triploid endosperm is where gene imprinting occurs most often, but aside from studies on Arabidopsis, little is known about gene imprinting in dicotyledons. In this study, we inspected genomic imprinting in castor bean (Ricinus communis) endosperm, which persists throughout seed development. After mapping out the polymorphic SNP loci between accessions ZB306 and ZB107, we generated deep sequencing RNA profiles of F1 hybrid seeds derived from reciprocal crosses. Using polymorphic SNP sites to quantify allele-specific expression levels, we identified 209 genes in reciprocal endosperms with potential parent-of-origin specific expression, including 200 maternally expressed genes and 9 paternally expressed genes. In total, 57 of the imprinted genes were validated via reverse transcriptase-polymerase chain reaction sequencing, and analysis of the genomic DNA methylation distribution between embryo and endosperm tissues showed significant hypomethylation in the endosperm and an enrichment of differentially methylated regions around the identified genes. Curiously, the expression of the imprinted genes was not tightly linked to DNA methylation. These results largely extended gene imprinting information existing in plants, providing potential directions for further research in gene imprinting. PMID:24799438

  4. Transcriptome-wide investigation of genomic imprinting in chicken.

    PubMed

    Frésard, Laure; Leroux, Sophie; Servin, Bertrand; Gourichon, David; Dehais, Patrice; Cristobal, Magali San; Marsaud, Nathalie; Vignoles, Florence; Bed'hom, Bertrand; Coville, Jean-Luc; Hormozdiari, Farhad; Beaumont, Catherine; Zerjal, Tatiana; Vignal, Alain; Morisson, Mireille; Lagarrigue, Sandrine; Pitel, Frédérique

    2014-04-01

    Genomic imprinting is an epigenetic mechanism by which alleles of some specific genes are expressed in a parent-of-origin manner. It has been observed in mammals and marsupials, but not in birds. Until now, only a few genes orthologous to mammalian imprinted ones have been analyzed in chicken and did not demonstrate any evidence of imprinting in this species. However, several published observations such as imprinted-like QTL in poultry or reciprocal effects keep the question open. Our main objective was thus to screen the entire chicken genome for parental-allele-specific differential expression on whole embryonic transcriptomes, using high-throughput sequencing. To identify the parental origin of each observed haplotype, two chicken experimental populations were used, as inbred and as genetically distant as possible. Two families were produced from two reciprocal crosses. Transcripts from 20 embryos were sequenced using NGS technology, producing ∼200 Gb of sequences. This allowed the detection of 79 potentially imprinted SNPs, through an analysis method that we validated by detecting imprinting from mouse data already published. However, out of 23 candidates tested by pyrosequencing, none could be confirmed. These results come together, without a priori, with previous statements and phylogenetic considerations assessing the absence of genomic imprinting in chicken. PMID:24452801

  5. Transcriptome-wide investigation of genomic imprinting in chicken

    PubMed Central

    Frésard, Laure; Leroux, Sophie; Servin, Bertrand; Gourichon, David; Dehais, Patrice; Cristobal, Magali San; Marsaud, Nathalie; Vignoles, Florence; Bed'hom, Bertrand; Coville, Jean-Luc; Hormozdiari, Farhad; Beaumont, Catherine; Zerjal, Tatiana; Vignal, Alain; Morisson, Mireille; Lagarrigue, Sandrine; Pitel, Frédérique

    2014-01-01

    Genomic imprinting is an epigenetic mechanism by which alleles of some specific genes are expressed in a parent-of-origin manner. It has been observed in mammals and marsupials, but not in birds. Until now, only a few genes orthologous to mammalian imprinted ones have been analyzed in chicken and did not demonstrate any evidence of imprinting in this species. However, several published observations such as imprinted-like QTL in poultry or reciprocal effects keep the question open. Our main objective was thus to screen the entire chicken genome for parental-allele-specific differential expression on whole embryonic transcriptomes, using high-throughput sequencing. To identify the parental origin of each observed haplotype, two chicken experimental populations were used, as inbred and as genetically distant as possible. Two families were produced from two reciprocal crosses. Transcripts from 20 embryos were sequenced using NGS technology, producing ∼200 Gb of sequences. This allowed the detection of 79 potentially imprinted SNPs, through an analysis method that we validated by detecting imprinting from mouse data already published. However, out of 23 candidates tested by pyrosequencing, none could be confirmed. These results come together, without a priori, with previous statements and phylogenetic considerations assessing the absence of genomic imprinting in chicken. PMID:24452801

  6. Loss of genomic imprinting in Drosophila clones.

    PubMed

    Haigh, Andrew J; Lloyd, Vett K

    2006-08-01

    Genomic imprinting is a process that genetically distinguishes maternal and paternal genomes, and can result in parent-of-origin-dependent monoallelic expression of a gene that is dependent on the parent of origin. As such, an otherwise functional maternally inherited allele may be silenced so that the gene is expressed exclusively from the paternal allele, or vice versa. Once thought to be restricted to mammals, genomic imprinting has been documented in angiosperm plants (J.L. Kermicle. 1970. Genetics, 66: 69-85), zebrafish (C.C. Martin and R. McGowan. 1995. Genet. Res. 65: 21-28), insects, and C. elegans (C.J. Bean, C.E. Schaner, and W.G. Kelly. 2004. Nat. Genet. 36: 100-105.). In each case, it appears to rely on differential chromatin structure. Aberrant imprinting has been implicated in various human cancers and has been detected in a number of cloned mammals, potentially limiting the usefulness of somatic nuclear transfer. Here we show that genomic imprinting associated with a mini-X chromosome is lost in Drosophila melanogaster clones. PMID:17036079

  7. Hypothesis: gonadal temperature influences sex-specific imprinting

    PubMed Central

    Donti, Emilio

    2014-01-01

    Various explanations have been advanced for the evolution of genomic imprinting, the most popular of these being the parental conflict hypothesis. However, while this theory may explain why there has been selection for imprinting certain genes, it does not explain how the maternal and paternal genomes can be distinguished from each other. Here, we hypothesize that the temperature at which male and female gonads are physiologically exposed could be, at least for some loci, the primary factor leading to the different imprinting between the sexes. PMID:25202325

  8. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

    PubMed

    Docherty, Louise E; Rezwan, Faisal I; Poole, Rebecca L; Turner, Claire L S; Kivuva, Emma; Maher, Eamonn R; Smithson, Sarah F; Hamilton-Shield, Julian P; Patalan, Michal; Gizewska, Maria; Peregud-Pogorzelski, Jaroslaw; Beygo, Jasmin; Buiting, Karin; Horsthemke, Bernhard; Soellner, Lukas; Begemann, Matthias; Eggermann, Thomas; Baple, Emma; Mansour, Sahar; Temple, I Karen; Mackay, Deborah J G

    2015-01-01

    Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting. PMID:26323243

  9. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

    PubMed Central

    Docherty, Louise E.; Rezwan, Faisal I.; Poole, Rebecca L.; Turner, Claire L. S.; Kivuva, Emma; Maher, Eamonn R.; Smithson, Sarah F.; Hamilton-Shield, Julian P.; Patalan, Michal; Gizewska, Maria; Peregud-Pogorzelski, Jaroslaw; Beygo, Jasmin; Buiting, Karin; Horsthemke, Bernhard; Soellner, Lukas; Begemann, Matthias; Eggermann, Thomas; Baple, Emma; Mansour, Sahar; Temple, I. Karen; Mackay, Deborah J. G.

    2015-01-01

    Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting. PMID:26323243

  10. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.

    PubMed

    Soejima, Hidenobu; Higashimoto, Ken

    2013-07-01

    Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders. PMID:23719190

  11. Changes in Parthenogenetic Imprinting Patterns during Reprogramming by Cell Fusion

    PubMed Central

    Jang, Hyun Sik; Hong, Yean Ju; Choi, Hyun Woo; Song, Hyuk; Byun, Sung June; Uhm, Sang Jun; Seo, Han Geuk; Do, Jeong Tae

    2016-01-01

    Differentiated somatic cells can be reprogrammed into the pluripotent state by cell-cell fusion. In the pluripotent state, reprogrammed cells may then self-renew and differentiate into all three germ layers. Fusion-induced reprogramming also epigenetically modifies the somatic cell genome through DNA demethylation, X chromosome reactivation, and histone modification. In this study, we investigated whether fusion with embryonic stem cells (ESCs) also reprograms genomic imprinting patterns in somatic cells. In particular, we examined imprinting changes in parthenogenetic neural stem cells fused with biparental ESCs, as well as in biparental neural stem cells fused with parthenogenetic ESCs. The resulting hybrid cells expressed the pluripotency markers Oct4 and Nanog. In addition, methylation of several imprinted genes except Peg3 was comparable between hybrid cells and ESCs. This finding indicates that reprogramming by cell fusion does not necessarily reverse the status of all imprinted genes to the state of pluripotent fusion partner. PMID:27232503

  12. Maintaining memory of silencing at imprinted differentially methylated regions.

    PubMed

    Voon, Hsiao P J; Gibbons, Richard J

    2016-05-01

    Imprinted genes are an exceptional cluster of genes which are expressed in a parent-of-origin dependent fashion. This allele-specific expression is dependent on differential DNA methylation which is established in the parental germlines in a sex-specific manner. The DNA methylation imprint is accompanied by heterochromatin modifications which must be continuously maintained through development. This review summarises the factors which are important for protecting the epigenetic modifications at imprinted differentially methylated regions (DMRs), including PGC7, ZFP57 and the ATRX/Daxx/H3.3 complex. We discuss how these factors maintain heterochromatin silencing, not only at imprinted DMRs, but also other heterochromatic regions in the genome. PMID:26883803

  13. Different yet similar: evolution of imprinting in flowering plants and mammals

    PubMed Central

    2014-01-01

    Genomic imprinting refers to a form of epigenetic gene regulation whereby alleles are differentially expressed in a parent-of-origin-dependent manner. Imprinting evolved independently in flowering plants and in therian mammals in association with the elaboration of viviparity and a placental habit. Despite the striking differences in plant and animal reproduction, genomic imprinting shares multiple characteristics between them. In both groups, imprinted expression is controlled, at least in part, by DNA methylation and chromatin modifications in cis-regulatory regions, and many maternally and paternally expressed genes display complementary dosage-dependent effects during embryogenesis. This suggests that genomic imprinting evolved in response to similar selective pressures in flowering plants and mammals. Nevertheless, there are important differences between plant and animal imprinting. In particular, genomic imprinting has been shown to be more flexible and evolutionarily labile in plants. In mammals, imprinted genes are organized mainly in highly conserved clusters, whereas in plants they occur in isolation throughout the genome and are affected by local gene duplications. There is a large degree of intra- and inter-specific variation in imprinted gene expression in plants. These differences likely reflect the distinct life cycles and the different evolutionary dynamics that shape plant and animal genomes. PMID:25165562

  14. A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms' tumourigenesis.

    PubMed

    Hancock, Anne L; Brown, Keith W; Moorwood, Kim; Moon, Hanlim; Holmgren, Claes; Mardikar, Sudhanshu H; Dallosso, Anthony R; Klenova, Elena; Loukinov, Dmitri; Ohlsson, Rolf; Lobanenkov, Victor V; Malik, Karim

    2007-02-01

    We have shown previously that AWT1 and WT1-AS are functionally imprinted in human kidney. In the adult kidney, expression of both transcripts is restricted to the paternal allele, with the silent maternal allele retaining methylation at the WT1 antisense regulatory region (WT1 ARR). Here, we report characterization of the WT1 ARR differentially methylated region and show that it contains a transcriptional silencer element acting on both the AWT1 and WT1-AS promoters. DNA methylation of the silencer results in increased transcriptional repression, and the silencer is also shown to be an in vitro and in vivo target site for the imprinting regulator protein CTCF. Binding of CTCF is methylation-sensitive and limited to the unmethylated silencer. Potentiation of the silencer activity is demonstrated after CTCF protein is knocked down, suggesting a novel silencer-blocking activity for CTCF. We also report assessment of WT1 ARR methylation in developmental and tumour tissues, including the first analysis of Wilms' tumour precursor lesions, nephrogenic rests. Nephrogenic rests show increases in methylation levels relative to foetal kidney and reductions relative to the adult kidney, together with biallelic expression of AWT1 and WT1-AS. Notably, the methylation status of CpG residues within the CTCF target site appears to distinguish monoallelic and biallelic expression states. Our data suggest that failure of methylation spreading at the WT1 ARR early in renal development, followed by imprint erasure, occurs during Wilms' tumourigenesis. We propose a model wherein imprinting defects at chromosome 11p13 may contribute to Wilms' tumourigenesis. PMID:17210670

  15. Molecularly Imprinted Membranes

    PubMed Central

    Trotta, Francesco; Biasizzo, Miriam; Caldera, Fabrizio

    2012-01-01

    Although the roots of molecularly imprinted polymers lie in the beginning of 1930s in the past century, they have had an exponential growth only 40–50 years later by the works of Wulff and especially by Mosbach. More recently, it was also proved that molecular imprinted membranes (i.e., polymer thin films) that show recognition properties at molecular level of the template molecule are used in their formation. Different procedures and potential application in separation processes and catalysis are reported. The influences of different parameters on the discrimination abilities are also discussed. PMID:24958291

  16. Genomic imprinting, action, and interaction of maternal and fetal genomes

    PubMed Central

    Keverne, Eric B.

    2015-01-01

    Mammalian viviparity (intrauterine development of the fetus) introduced a new dimension to brain development, with the fetal hypothalamus and fetal placenta developing at a time when the fetal placenta engages hypothalamic structures of the maternal generation. Such transgenerational interactions provide a basis for ensuring optimal maternalism in the next generation. This success has depended on genomic imprinting and a biased role of the matriline. Maternal methylation imprints determine parent of origin expression of genes fundamental to both placental and hypothalamic development. The matriline takes a further leading role for transgenerational reprogramming of these imprints. Developmental errors are minimized by the tight control that imprinted genes have on regulation of downstream evolutionary expanded gene families important for placental and hypothalamic development. Imprinted genes themselves have undergone purifying selection, providing a framework of stability for in utero development with most growth variance occurring postnatally. Mothers, not fathers, take the lead in the endocrinological and behavior adaptations that nurture, feed, and protect the infant. In utero coadaptive development of the placenta and hypothalamus has thus required a concomitant development to ensure male masculinization. Only placental male mammals evolved the sex determining SRY, which activates Sox9 for testes formation. SRY is a hybrid gene of Dgcr8 expressed in the developing placenta and Sox3 expressed in hypothalamic development. This hybridization of genes that take their origin from the placenta and hypothalamus has enabled critical in utero timing for the development of fetal Leydig cells, and hence testosterone production for hypothalamic masculinization. PMID:25404322

  17. Detection of Loss of Imprinting by Pyrosequencing®.

    PubMed

    Tabano, Silvia; Bonaparte, Eleonora; Miozzo, Monica

    2015-01-01

    Genomic imprinting is an epigenetically regulated process determining allele-specific expression in a parent-of-origin dependent manner. Altered expression of imprinted genes characterizes numerous congenital diseases including Beckwith-Wiedemann, Silver-Russell, Angelman, and Prader-Willi syndromes as well as acquired disorders such as cancer. The detection of imprinting alterations has important translational implications in clinics and the application of the Pyrosequencing(®) technology offers the possibility to identify accurately also subtle modifications in allele-specific expression and in DNA methylation levels.Here, we describe two methods to investigate genomic imprinting defects (loss of imprinting, LOI) using Pyrosequencing: (1) Allele-specific expression analysis based on single nucleotide polymorphism (SNP), and (2) quantification of DNA methylation.The protocol for the quantification of the allele-specific expression is carried out by analyzing an informative SNP located within the transcribed portion of an imprinted gene. The method includes the cDNA amplification of the region containing the SNP and the Pyrosequencing-based analysis for the quantitative allelic discrimination comparing the ratio of the two alleles.The second protocol allows the accurate quantification of the DNA methylation levels at the Imprinting Control Regions (ICRs). Imprinted genes are clustered in chromosomal regions and their expression is mainly regulated by DNA methylation at CpG sites located within the ICRs. After bisulfite modification of the genomic DNA, the region of interest is amplified by PCR and analyzed by Pyrosequencing. The methylation value at each CpG site is calculated by the CpG software, which determines the ratio of the incorporation of "C" and "T" and converts the value in methylation percentage. PMID:26103904

  18. Genomic imprinting and the evolutionary psychology of human kinship

    PubMed Central

    Haig, David

    2011-01-01

    Genomic imprinting is predicted to influence behaviors that affect individuals to whom an actor has different degrees of matrilineal and patrilineal kinship (asymmetric kin). Effects of imprinted genes are not predicted in interactions with nonrelatives or with individuals who are equally related to the actor's maternally and paternally derived genes (unless a gene also has pleiotropic effects on fitness of asymmetric kin). Long-term mating bonds are common in most human populations, but dissolution of marriage has always affected a significant proportion of mated pairs. Children born in a new union are asymmetric kin of children born in a previous union. Therefore, the innate dispositions of children toward parents and sibs are expected to be sensitive to cues of marital stability, and these dispositions may be subject to effects of imprinted genes. PMID:21690414

  19. Prader-Willi Syndrome: Obesity due to Genomic Imprinting

    PubMed Central

    Butler, Merlin G

    2011-01-01

    Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS. PMID:22043168

  20. Bypassing genomic imprinting allows seed development.

    PubMed

    Nowack, Moritz K; Shirzadi, Reza; Dissmeyer, Nico; Dolf, Andreas; Endl, Elmar; Grini, Paul E; Schnittger, Arp

    2007-05-17

    In developing progeny of mammals the two parental genomes are differentially expressed according to imprinting marks, and embryos with only a uniparental genetic contribution die. Gene expression that is dependent on the parent of origin has also been observed in the offspring of flowering plants, and mutations in the imprinting machinery lead to embryonic lethality, primarily affecting the development of the endosperm-a structure in the seed that nourishes the embryo, analogous to the function of the mammalian placenta. Here we have generated Arabidopsis thaliana seeds in which the endosperm is of uniparental, that is, maternal, origin. We demonstrate that imprinting in developing seeds can be bypassed and viable albeit smaller seedlings can develop from seeds lacking a paternal contribution to the endosperm. Bypassing is only possible if the mother is mutant for any of the FIS-class genes, which encode Polycomb group chromatin-modifying factors. Thus, these data provide functional evidence that the action of the FIS complex balances the contribution of the paternal genome. As flowering plants have evolved a special reproduction system with a parallel fusion of two female with two male gametes, our findings support the hypothesis that only with the evolution of double fertilization did the action of the FIS genes become a requirement for seed development. Furthermore, our data argue for a gametophytic origin of endosperm in flowering plants, thereby supporting a hypothesis raised in 1900 by Eduard Strasburger. PMID:17468744

  1. mRNA imprinting

    PubMed Central

    2011-01-01

    Following its synthesis in the nucleus, mRNA undergoes various stages that are critical for the proper synthesis, localization and possibly functionality of its encoded protein. Recently, we have shown that two RNA polymerase II (Pol II) subunits, Rpb4p and Rpb7p, associate with the nascent transcript co-transcriptionally. This “mRNA imprinting” lasts throughout the mRNA lifetime and is required for proper regulation of all major stages that the mRNA undergoes. Other possible cases of co-transcriptional imprinting are discussed. Since mRNAs can be transported from the synthesizing cell to other cells, we propose that mRNA imprinting can also affect the phenotype of the recipient cells. This can be viewed as “mRNA-based epigenetics.” PMID:21686103

  2. Imprinting artificial magnetic structures.

    SciTech Connect

    Lohstroh, W.

    1998-09-25

    Recently we created La/Fe multilayers with a helical magnetic structure imprinted from the conditions of growth rather than by the magnetic interactions between layers. Each sublayer was 30{angstrom} thick, and during deposition the sample was rotated in an external field of 3 Oe. a field strong enough to magnetize the Fe layer being deposited but not sufficient to perturb the magnetization of the Fe layers already grown. As a result adjacent Fe layers formed a helical structure with a chirality and periodicity determined by the rotational direction and speed of the substrate and the rate of deposition. Following this discovery, an extensive set of experiments (mainly using Kerr effect magnetometry and polarized neutron reflectivity) was undertaken to ascertain the stability of imprinted magnetic structures, and to understand the onset of magnetization during growth. La/Fe imprinted helical magnetic structures (of different La and Fe thicknesses) were found to be stable in time and to be permanently erased only by magnetic fields larger than 90 Oe.

  3. In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

    PubMed

    Mayo, Sonia; Monfort, Sandra; Roselló, Mónica; Oltra, Silvestre; Orellana, Carmen; Martínez, Francisco

    2015-01-01

    Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders. PMID:26106604

  4. In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients

    PubMed Central

    Mayo, Sonia; Monfort, Sandra; Roselló, Mónica; Oltra, Silvestre; Orellana, Carmen; Martínez, Francisco

    2015-01-01

    Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders. PMID:26106604

  5. Genomic Imprinting and the Expression of Affect in Angelman Syndrome: What's in the Smile?

    ERIC Educational Resources Information Center

    Oliver, Chris; Horsler, Kate; Berg, Katy; Bellamy, Gail; Dick, Katie; Griffiths, Emily

    2007-01-01

    Background: Kinship theory (or the genomic conflict hypothesis) proposes that the phenotypic effects of genomic imprinting arise from conflict between paternally and maternally inherited alleles. A prediction arising for social behaviour from this theory is that imbalance in this conflict resulting from a deletion of a maternally imprinted gene,…

  6. The origin and evolution of genomic imprinting and viviparity in mammals

    PubMed Central

    Renfree, Marilyn B.; Suzuki, Shunsuke; Kaneko-Ishino, Tomoko

    2013-01-01

    Genomic imprinting is widespread in eutherian mammals. Marsupial mammals also have genomic imprinting, but in fewer loci. It has long been thought that genomic imprinting is somehow related to placentation and/or viviparity in mammals, although neither is restricted to mammals. Most imprinted genes are expressed in the placenta. There is no evidence for genomic imprinting in the egg-laying monotreme mammals, despite their short-lived placenta that transfers nutrients from mother to embryo. Post natal genomic imprinting also occurs, especially in the brain. However, little attention has been paid to the primary source of nutrition in the neonate in all mammals, the mammary gland. Differentially methylated regions (DMRs) play an important role as imprinting control centres in each imprinted region which usually comprises both paternally and maternally expressed genes (PEGs and MEGs). The DMR is established in the male or female germline (the gDMR). Comprehensive comparative genome studies demonstrated that two imprinted regions, PEG10 and IGF2-H19, are conserved in both marsupials and eutherians and that PEG10 and H19 DMRs emerged in the therian ancestor at least 160 Ma, indicating the ancestral origin of genomic imprinting during therian mammal evolution. Importantly, these regions are known to be deeply involved in placental and embryonic growth. It appears that most maternal gDMRs are always associated with imprinting in eutherian mammals, but emerged at differing times during mammalian evolution. Thus, genomic imprinting could evolve from a defence mechanism against transposable elements that depended on DNA methylation established in germ cells. PMID:23166401

  7. Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation.

    PubMed

    Bonakdar, Shahin; Mahmoudi, Morteza; Montazeri, Leila; Taghipoor, Mojtaba; Bertsch, Arnaud; Shokrgozar, Mohammad Ali; Sharifi, Shahriar; Majidi, Mohammad; Mashinchian, Omid; Hamrang Sekachaei, Mohammad; Zolfaghari, Pegah; Renaud, Philippe

    2016-06-01

    Differentiation of stem cells into mature cells through the use of physical approaches is of great interest. Here, we prepared smart nanoenvironments by cell-imprinted substrates based on chondrocytes, tenocytes, and semifibroblasts as templates and demonstrated their potential for differentiation, redifferentiation, and transdifferentiation. Analysis of shape and upregulation/downregulation of specific genes of stem cells, which were seeded on these cell-imprinted substrates, confirmed that imprinted substrates have the capability to induce specific shapes and molecular characteristics of the cell types that were used as templates for cell-imprinting. Interestingly, immunofluorescent staining of a specific protein in chondrocytes (i.e., collagen type II) confirmed that adipose-derived stem cells, semifibroblasts, and tenocytes can acquire the chondrocyte phenotype after a 14 day culture on chondrocyte-imprinted substrates. In summary, we propose that common polystyrene tissue culture plates can be replaced by this imprinting technique as an effective and promising way to regulate any cell phenotype in vitro with significant potential applications in regenerative medicine and cell-based therapies. PMID:27196338

  8. Comparative Anatomy of Chromosomal Domains with Imprinted and Non-Imprinted Allele-Specific DNA Methylation

    PubMed Central

    Kerkel, Kristi; Yale, Alexander; Yotova, Iveta; Drost, Natalia; Lax, Simon; Nhan-Chang, Chia-Ling; Powell, Charles; Borczuk, Alain; Aviv, Abraham; Wapner, Ronald; Chen, Xiaowei; Nagy, Peter L.; Schork, Nicholas; Do, Catherine; Torkamani, Ali; Tycko, Benjamin

    2013-01-01

    Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM. PMID:24009515

  9. Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation.

    PubMed

    Paliwal, Anupam; Temkin, Alexis M; Kerkel, Kristi; Yale, Alexander; Yotova, Iveta; Drost, Natalia; Lax, Simon; Nhan-Chang, Chia-Ling; Powell, Charles; Borczuk, Alain; Aviv, Abraham; Wapner, Ronald; Chen, Xiaowei; Nagy, Peter L; Schork, Nicholas; Do, Catherine; Torkamani, Ali; Tycko, Benjamin

    2013-08-01

    Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM. PMID:24009515

  10. Molecularly imprinted polymers for mycotoxins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Molecularly imprinted polymers (MIPs) are a class of synthetic receptors capable of selective recognition of analytes. Recent developments in imprinting technology have made it possible to apply this technology in a range of applications, including mycotoxin detection. Structure-activity relations...

  11. Coadaptation and conflict, misconception and muddle, in the evolution of genomic imprinting

    PubMed Central

    Haig, D

    2014-01-01

    Common misconceptions of the ‘parental conflict' theory of genomic imprinting are addressed. Contrary to widespread belief, the theory defines conditions for cooperation as well as conflict in mother–offspring relations. Moreover, conflict between genes of maternal and paternal origin is not the same as conflict between mothers and fathers. In theory, imprinting can evolve either because genes of maternal and paternal origin have divergent interests or because offspring benefit from a phenotypic match, or mismatch, to one or other parent. The latter class of models usually require maintenance of polymorphism at imprinted loci for the maintenance of imprinted expression. The conflict hypothesis does not require maintenance of polymorphism and is therefore a more plausible explanation of evolutionarily conserved imprinting. PMID:24129605

  12. Imprinting of opossum Igf2r in the absence of differential methylation and air.

    PubMed

    Weidman, Jennifer R; Dolinoy, Dana C; Maloney, Kristin A; Cheng, Jan-Fang; Jirtle, Randy L

    2006-01-01

    Phylogenetic comparison of extant mammals with divergent imprint status is a powerful method for identifying critical components of imprint regulation at individual loci. The entire genomic region of Igf2r in the imprinted marsupials, Didelphis virginiana and Monodelphis domestica, and the non-imprinted monotreme, Ornithorhynchus anatinus, was isolated and sequenced. Genetic and epigenetic comparisons of over 160 kb of sequence were then performed in five distinct mammalian species. Surprisingly, opossum Igf2r is imprinted and maternally expressed despite the absence of the intron 2 CpG island (CpG2), antisense Igf2r RNA (Air) and differential methylation of the promoter (CpG1) required for imprinting of this gene in mice. These findings demonstrate that the genomic elements necessary for imprinted Igf2r expression in eutherians are not required for imprinting of this locus in metatherians. Thus, the regulatory mechanisms of Igf2r imprinting did not evolve convergently within the Therian subclass of mammals. PMID:17998818

  13. Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization.

    PubMed

    Brioude, Frederic; Netchine, Irène; Praz, Francoise; Le Jule, Marilyne; Calmel, Claire; Lacombe, Didier; Edery, Patrick; Catala, Martin; Odent, Sylvie; Isidor, Bertrand; Lyonnet, Stanislas; Sigaudy, Sabine; Leheup, Bruno; Audebert-Bellanger, Séverine; Burglen, Lydie; Giuliano, Fabienne; Alessandri, Jean-Luc; Cormier-Daire, Valérie; Laffargue, Fanny; Blesson, Sophie; Coupier, Isabelle; Lespinasse, James; Blanchet, Patricia; Boute, Odile; Baumann, Clarisse; Polak, Michel; Doray, Berenice; Verloes, Alain; Viot, Géraldine; Le Bouc, Yves; Rossignol, Sylvie

    2015-09-01

    Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS. PMID:26077438

  14. Protein imprinting in polyacrylamide-based gels

    PubMed Central

    Zayats, Maya; Brenner, Andrew J.; Searson, Peter C.

    2015-01-01

    Protein imprinting in hydrogels is a method to produce materials capable of selective recognition and capture of a target protein. Here we report on the imprinting of fluorescently-labeled maltose binding protein (MBP) in acrylamide (AAm)/N-isopropylacrylamide (NIPAm) hydrogels. The targeting efficiency and selectivity of protein recognition is usually characterized by the imprinting factor, which in the simplest case is the ratio of protein uptake in an imprinted film divided by the uptake by the corresponding non-imprinted film. Our objective in this work is to study the dynamics of protein binding and elution in imprinted and non-imprinted films to elucidate the processes that control protein recognition. Protein elution from imprinted and non-imprinted films suggests that imprinting results in sites with a distribution of binding energies, and that only a relatively small fraction of these sites exhibit strong binding. PMID:25034963

  15. Protein imprinting in polyacrylamide-based gels.

    PubMed

    Zayats, Maya; Brenner, Andrew J; Searson, Peter C

    2014-10-01

    Protein imprinting in hydrogels is a method to produce materials capable of selective recognition and capture of a target protein. Here we report on the imprinting of fluorescently-labeled maltose binding protein (MBP) in acrylamide (AAm)/N-isopropylacrylamide (NIPAm) hydrogels. The targeting efficiency and selectivity of protein recognition is usually characterized by the imprinting factor, which in the simplest case is the ratio of protein uptake in an imprinted film divided by the uptake by the corresponding non-imprinted film. Our objective in this work is to study the dynamics of protein binding and elution in imprinted and non-imprinted films to elucidate the processes that control protein recognition. Protein elution from imprinted and non-imprinted films suggests that imprinting results in sites with a distribution of binding energies, and that only a relatively small fraction of these sites exhibit strong binding. PMID:25034963

  16. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders.

    PubMed

    Poole, Rebecca L; Docherty, Louise E; Al Sayegh, Abeer; Caliebe, Almuth; Turner, Claire; Baple, Emma; Wakeling, Emma; Harrison, Lucy; Lehmann, Anna; Temple, I Karen; Mackay, Deborah J G

    2013-09-01

    Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management. PMID:23913548

  17. Tissue specificity and variability of imprinted IGF2 expression in humans

    SciTech Connect

    Giannoukakis, N.; Rouleau, G.; Polychronakos, C.

    1994-09-01

    Parental genomic imprinting refers to the phenomenon where expression of a gene copy depends on the sex of the parent from which it is derived. The human insulin-like growth factor II gene, IGF2, is parentally imprinted with the paternal gene copy exclusively expressed in fetal and term placenta as well as in fetal kidney. In mice, imprinted IGF2 expression is tissue-specific. In a preliminary approach to investigate tissue-specific IGF2 imprinting in humans, we evaluated allele-specific expression in four samples of umbilical cord blood leukocytes of fetuses found to imprint IGF2 in placenta. IGF2 mRNA transcripts from the gene copy transmitted from each parent were distinguished using a transcribed ApaI polymorphism by performing reverse transcription-PCR on total RNA from cord blood leukocytes. Postnatal peripheral blood was examined using the same method. Of 77 informative individuals, 68 expressed both IGF2 copies, but 9 individuals showed unambiguous monoallelic expression. Two individuals from each category were screened again and the results were identical. These data indicate that imprinted IGF2 expression is tissue-specific and show variability of IGF2 imprinting among individuals. This variability may be genetic. We are in the process of screening large pedigrees to test this hypothesis.

  18. CRITICAL EXPERIMENTS TO DETERMINE IF EARLY NUTRITIONAL INFLUENCES ON EPIGENETIC MECHANISMS CAUSE METABOLIC IMPRINTING IN HUMANS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic imprinting occurs when nutritional influences during critical periods of development cause specific metabolic adaptations that persist to adulthood. Epigenetic mechanisms, which regulate the broad diversity of tissue-specific gene expression, are established during development and largely ...

  19. Detection of imprinting mutations in Angelman syndrome using a probe for exon {alpha} of SNRPN

    SciTech Connect

    Beuten, J.; Sutcliffe, J.S.; Casey, B.M.

    1996-05-17

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct clinical disorders resulting from deficiency of paternal (PWS) or maternal (AS) expression of imprinted genes within chromosome 15q11-q13. 15 refs., 1 fig.

  20. Genomic imprinting proposed as a surveillance mechanism for chromosome loss.

    PubMed Central

    Thomas, J H

    1995-01-01

    One consequence of genomic imprinting is that loss of the transcriptionally active chromosomal homologue causes a change in gene expression that might permit surveillance of chromosome-loss events. Possible selective advantages of such surveillance include protection against cancer and early elimination of monosomic and trisomic fetuses. Potential mechanisms for such surveillance are discussed. PMID:7831314

  1. Conversion of genomic imprinting by reprogramming and redifferentiation.

    PubMed

    Kim, Min Jung; Choi, Hyun Woo; Jang, Hyo Jin; Chung, Hyung Min; Arauzo-Bravo, Marcos J; Schöler, Hans R; Do, Jeong Tae

    2013-06-01

    Induced pluripotent stem cells (iPSCs), generated from somatic cells by overexpression of transcription factors Oct4, Sox2, Klf4 and c-Myc have the same characteristics as pluripotent embryonic stem cells (ESCs). iPSCs reprogrammed from differentiated cells undergo epigenetic modification during reprogramming, and ultimately acquire a similar epigenetic state to that of ESCs. In this study, these epigenetic changes were observed in reprogramming of uniparental parthenogenetic somatic cells. The parthenogenetic pattern of imprinted genes changes during the generation of parthenogenetic maternal iPSCs (miPSCs), a process referred to as pluripotent reprogramming. We determined whether altered imprinted genes are maintained or revert to the parthenogenetic state when the reprogrammed cells are redifferentiated into specialized cell types. To address this question, we redifferentiated miPSCs into neural stem cells (miPS-NSCs) and compared them with biparental female NSCs (fNSCs) and parthenogenetic NSCs (pNSCs). We found that pluripotent reprogramming of parthenogenetic somatic cells could reset parthenogenetic DNA methylation patterns in imprinted genes, and that alterations in DNA methylation were maintained even after miPSCs were redifferentiated into miPS-NSCs. Notably, maternally methylated imprinted genes (Peg1, Peg3, Igf2r, Snrpn and Ndn), whose differentially methylated regions were fully methylated in pNSCs, were demethylated and their expression levels were found to be close to the levels in normal biparental fNSCs after reprogramming and redifferentiation. Our findings suggest that pluripotent reprogramming of parthenogenetic somatic cells followed by redifferentiation leads to changes in DNA methylation of imprinted genes and the reestablishment of gene expression levels to those of normal biparental cells. PMID:23525019

  2. Programmable imprint lithography template

    DOEpatents

    Cardinale, Gregory F.; Talin, Albert A.

    2006-10-31

    A template for imprint lithography (IL) that reduces significantly template production costs by allowing the same template to be re-used for several technology generations. The template is composed of an array of spaced-apart moveable and individually addressable rods or plungers. Thus, the template can be configured to provide a desired pattern by programming the array of plungers such that certain of the plungers are in an "up" or actuated configuration. This arrangement of "up" and "down" plungers forms a pattern composed of protruding and recessed features which can then be impressed onto a polymer film coated substrate by applying a pressure to the template impressing the programmed configuration into the polymer film. The pattern impressed into the polymer film will be reproduced on the substrate by subsequent processing.

  3. Manganese uptake of imprinted polymers

    DOE Data Explorer

    Susanna Ventura

    2015-09-30

    Batch tests of manganese imprinted polymers of variable composition to assess their ability to extract lithium and manganese from synthetic brines at T=45C . Data on manganese uptake for two consecutive cycles are included.

  4. Polyandry, life-history trade-offs and the evolution of imprinting at Mendelian loci.

    PubMed

    Mills, Walter; Moore, Tom

    2004-12-01

    Genomic imprinting causes parental origin-dependent differential expression of a small number of genes in mammalian and angiosperm plant embryos, resulting in non-Mendelian inheritance of phenotypic traits. The "conflict" theory of the evolution of imprinting proposes that reduced genetic relatedness of paternally, relative to maternally, derived alleles in offspring of polygamous females supports parental sex-specific selection at gene loci that influence maternal investment. While the theory's physiological predictions are well supported by observation, the requirement of polyandry in the evolution of imprinting from an ancestral Mendelian state has not been comprehensively analyzed. Here, we use diallelic models to examine the influence of various degrees of polyandry on the evolution of both Mendelian and imprinted autosomal gene loci that influence trade-offs between maternal fecundity and offspring viability. We show that, given a plausible assumption on the physiological relationship between maternal fecundity and offspring viability, low levels of polyandry are sufficient to reinforce exclusively the fixation of "greedy" paternally imprinted alleles that increase offspring viability at the expense of maternal fecundity and "thrifty" maternally imprinted alleles of opposite effect. We also show that, for all levels of polyandry, Mendelian alleles at genetic loci that influence the trade-off between maternal fecundity and offspring viability reach an evolutionary stable state, whereas pairs of reciprocally imprinted alleles do not. PMID:15611195

  5. Genomic Imprinting of Grb10 : Coadaptation or Conflict?

    PubMed Central

    Wilkins, Jon F.

    2014-01-01

    Mammalian development involves significant interactions between offspring and mother. But is this interaction a carefully coordinated effort by two individuals with a common goal—offspring survival? Or is it an evolutionary battleground (a central idea in our understanding of reproduction). The conflict between parents and offspring extends to an offspring's genes, where paternally inherited genes favor demanding more from the mother, while maternally inherited genes favor restraint. This “intragenomic conflict” (among genes within a genome) is the dominant evolutionary explanation for “genomic imprinting.” But a new study in PLOS Biology provides support for a different perspective: that imprinting might facilitate coordination between mother and offspring. According to this “coadaptation theory,” paternally inherited genes might be inactivated because maternally inherited genes are adapted to function harmoniously with the mother. As discussed in this article, the growth effects associated with the imprinted gene Grb10 are consistent with this idea, but it remains to be seen just how general the pattern is. PMID:24586115

  6. DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation

    PubMed Central

    2013-01-01

    Background Genomic imprinting is an epigenetically regulated process wherein genes are expressed in a parent-of-origin specific manner. Many imprinted genes were initially identified in mice; some of these were subsequently shown not to be imprinted in humans. Such discrepancy reflects developmental, morphological and physiological differences between mouse and human tissues. This is particularly relevant for the placenta. Study of genomic imprinting thus needs to be carried out in a species and developmental stage-specific manner. We describe here a new strategy to study allele-specific DNA methylation in the human placenta for the discovery of novel imprinted genes. Results Using this methodology, we confirmed 16 differentially methylated regions (DMRs) associated with known imprinted genes. We chose 28 genomic regions for further testing and identified two imprinted genes (DNMT1 and AIM1). Both genes showed maternal allele-specific methylation and paternal allele-specific transcription. Imprinted expression for AIM1 was conserved in the cynomolgus macaque placenta, but not in other macaque tissues or in the mouse. Conclusions Our study indicates that while there are many genomic regions with allele-specific methylation in tissues like the placenta, only a small sub-set of them are associated with allele-specific transcription, suggesting alternative functions for such genomic regions. Nonetheless, novel tissue-specific imprinted genes remain to be discovered in humans. Their identification may help us better understand embryonic and fetal development. PMID:24094292

  7. Recent acquisition of imprinting at the rodent Sfmbt2 locus correlates with insertion of a large block of miRNAs

    PubMed Central

    2011-01-01

    Background The proximal region of murine Chr 2 has long been known to harbour one or more imprinted genes from classic genetic studies involving reciprocal translocations. No imprinted gene had been identified from this region until our study demonstrated that the PcG gene Sfmbt2 is expressed from the paternally inherited allele in early embryos and extraembryonic tissues. Imprinted genes generally reside in clusters near elements termed Imprinting Control Regions (ICRs), suggesting that Sfmbt2 might represent an anchor for a new imprinted domain. Results We analyzed allelic expression of approximately 20 genes within a 3.9 Mb domain and found that Sfmbt2 and an overlapping non-coding antisense transcript are the only imprinted genes in this region. These transcripts represent a very narrow imprinted gene locus. We also demonstrate that rat Sfmbt2 is imprinted in extraembryonic tissues. An interesting feature of both mouse and rat Sfmbt2 genes is the presence of a large block of miRNAs in intron 10. Other mammals, including the bovine, lack this block of miRNAs. Consistent with this association, we show that human and bovine Sfmbt2 are biallelic. Other evidence indicates that pig Sfmbt2 is also not imprinted. Further strengthening the argument for recent evolution of Sfmbt2 is our demonstration that a more distant muroid rodent, Peromyscus also lacks imprinting and the block of miRNAs. Conclusions These observations are consistent with the hypothesis that the block of miRNAs are driving imprinting at this locus. Our results are discussed in the context of ncRNAs at other imprinted loci. Accession numbers for Peromyscus cDNA and intron 10 genomic DNA are [Genbank:HQ416417 and Genbank:HQ416418], respectively. PMID:21510876

  8. Rapid Evolution of Genomic Imprinting in Two Species of the Brassicaceae.

    PubMed

    Hatorangan, Marcelinus R; Laenen, Benjamin; Steige, Kim A; Slotte, Tanja; Köhler, Claudia

    2016-08-01

    Genomic imprinting is an epigenetic phenomenon occurring in mammals and flowering plants that causes genes to adopt a parent-of-origin-specific mode of expression. While the imprinting status of genes is well conserved in mammals, clear estimates for the degree of conservation were lacking in plants. We therefore analyzed the genome-wide imprinting status of Capsella rubella, which shared a common recent ancestor with Arabidopsis thaliana ∼10 to 14 million years ago. However, only ∼14% of maternally expressed genes (MEGs) and ∼29% of paternally expressed genes (PEGs) in C. rubella were commonly imprinted in both species, revealing that genomic imprinting is a rapidly evolving phenomenon in plants. Nevertheless, conserved PEGs exhibited signs of selection, suggesting that a subset of imprinted genes play an important functional role and are therefore maintained in plants. Like in Arabidopsis, PEGs in C. rubella are frequently associated with the presence of transposable elements that preferentially belong to helitron and MuDR families. Our data further reveal that MEGs and PEGs differ in their targeting by 24-nucleotide small RNAs and asymmetric DNA methylation, suggesting different mechanisms establishing DNA methylation at MEGs and PEGs. PMID:27465027

  9. Tet-mediated imprinting erasure in H19 locus following reprogramming of spermatogonial stem cells to induced pluripotent stem cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Selective methylation of CpG islands at imprinting control regions (ICR) determines the monoparental expression of a subset of genes. The imprinting marks are protected from global demethylation taking place during pre-implantation development before being reset in primordial germ cells. However, it...

  10. BENJAMIN FRANKLIN'S MEDICAL IMPRINTS.

    PubMed

    CANTU, J Q

    1965-01-01

    The printing house of Benjamin Franklin produced several works of a medical nature in Colonial America at a time when very few medical treatises were being written or printed. Benjamin Franklin was also indirectly responsible for the founding of the first medical library in this country. For these reasons he was, in addition to his many other talents, an early contributor to American medical literature. Included in this bibliography are all the known medical books, pamphlets, and broadsides in English with Benjamin Franklin's name in the imprint, issued in America. These eighteen titles span the years 1732 to 1765 and are presented chronologically with indications of their relation to the practice and practitioners of Colonial medicine. Benjamin Franklin's press produced as wide a variety of contributions as did his versatile life, and the early history of medicine in this country bears the influence of both.I am pleased with your scheme of a Medical Library at the Hospital, and I fancy I can procure you some donations among my medical friends here, if you will send me a catalogue of what books you already have. Enclosed I send you the only book of the kind in my possession here, having just received it as a present from the author.-Benjamin Franklin to Dr. Cadwallader Evans, London, May 5, 1767 (1). PMID:14223741

  11. Benjamin Franklin's Medical Imprints

    PubMed Central

    Cantu, Jane Quale

    1965-01-01

    The printing house of Benjamin Franklin produced several works of a medical nature in Colonial America at a time when very few medical treatises were being written or printed. Benjamin Franklin was also indirectly responsible for the founding of the first medical library in this country. For these reasons he was, in addition to his many other talents, an early contributor to American medical literature. Included in this bibliography are all the known medical books, pamphlets, and broadsides in English with Benjamin Franklin's name in the imprint, issued in America. These eighteen titles span the years 1732 to 1765 and are presented chronologically with indications of their relation to the practice and practitioners of Colonial medicine. Benjamin Franklin's press produced as wide a variety of contributions as did his versatile life, and the early history of medicine in this country bears the influence of both. I am pleased with your scheme of a Medical Library at the Hospital, and I fancy I can procure you some donations among my medical friends here, if you will send me a catalogue of what books you already have. Enclosed I send you the only book of the kind in my possession here, having just received it as a present from the author.—Benjamin Franklin to Dr. Cadwallader Evans, London, May 5, 1767 (1). PMID:14223741

  12. Relationship between the IQ of People with Prader-Willi Syndrome and that of Their Siblings: Evidence for Imprinted Gene Effects

    ERIC Educational Resources Information Center

    Whittington, J.; Holland, A.; Webb, T.

    2009-01-01

    Background: Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs.…

  13. Evidence for local regulatory control of escape from imprinted X chromosome inactivation.

    PubMed

    Mugford, Joshua W; Starmer, Joshua; Williams, Rex L; Calabrese, J Mauro; Mieczkowski, Piotr; Yee, Della; Magnuson, Terry

    2014-06-01

    X chromosome inactivation (XCI) is an epigenetic process that almost completely inactivates one of two X chromosomes in somatic cells of mammalian females. A few genes are known to escape XCI and the mechanism for this escape remains unclear. Here, using mouse trophoblast stem (TS) cells, we address whether particular chromosomal interactions facilitate escape from imprinted XCI. We demonstrate that promoters of genes escaping XCI do not congregate to any particular region of the genome in TS cells. Further, the escape status of a gene was uncorrelated with the types of genomic features and gene activity located in contacted regions. Our results suggest that genes escaping imprinted XCI do so by using the same regulatory sequences as their expressed alleles on the active X chromosome. We suggest a model where regulatory control of escape from imprinted XCI is mediated by genomic elements located in close linear proximity to escaping genes. PMID:24653000

  14. Evidence for Local Regulatory Control of Escape from Imprinted X Chromosome Inactivation

    PubMed Central

    Mugford, Joshua W.; Starmer, Joshua; Williams, Rex L.; Calabrese, J. Mauro; Mieczkowski, Piotr; Yee, Della; Magnuson, Terry

    2014-01-01

    X chromosome inactivation (XCI) is an epigenetic process that almost completely inactivates one of two X chromosomes in somatic cells of mammalian females. A few genes are known to escape XCI and the mechanism for this escape remains unclear. Here, using mouse trophoblast stem (TS) cells, we address whether particular chromosomal interactions facilitate escape from imprinted XCI. We demonstrate that promoters of genes escaping XCI do not congregate to any particular region of the genome in TS cells. Further, the escape status of a gene was uncorrelated with the types of genomic features and gene activity located in contacted regions. Our results suggest that genes escaping imprinted XCI do so by using the same regulatory sequences as their expressed alleles on the active X chromosome. We suggest a model where regulatory control of escape from imprinted XCI is mediated by genomic elements located in close linear proximity to escaping genes. PMID:24653000

  15. Epigenetic silencing of genes and microRNAs within the imprinted Dlk1-Dio3 region at human chromosome 14.32 in giant cell tumor of bone

    PubMed Central

    2014-01-01

    Background Growing evidence exists that the neoplastic stromal cell population (GCTSC) within giant cell tumors (GCT) originates from mesenchymal stem cells (MSC). In a previous study we identified a microRNA signature that differentiates between these cell types. Five differentially expressed microRNAs are located within the Dlk1-Dio3 region on chromosome 14. Aberrant regulation within this region is known to influence cell growth, differentiation and the development of cancer. The aim of this study was to elucidate the involvement of deregulations within the Dlk1-Dio3 region in GCT pathogenesis. Methods Quantitative gene and microRNA expression analyses were performed on GCTSCs and MSCs with or without treatment with epigenetic modifiers. Methylation analysis of differentially methylated regions was performed by bisulfite sequencing. Results In addition to microRNA silencing we detected a significant downregulation of Dlk1, Meg3 and Meg8 in GCTSCs compared to MSCs. DNA methylation analyses of the Meg3-DMR and IG-DMR revealed a frequent hypermethylation within the IG-DMR in GCTs. Epigenetic modification could restore expression of some but not all analyzed genes and microRNAs suggesting further regulatory mechanisms. Conclusion Epigenetic silencing of genes and microRNAs within the Dlk1-Dio3 region is a common event in GCTSCs, in part mediated by hypermethylation within the IG-DMR. The identified genes, micro RNAs and microRNA target genes might be valuable targets for the development of improved strategies for GCT diagnosis and therapy. PMID:25005035

  16. Direct Imprinting of Liquid Silicon.

    PubMed

    Masuda, Takashi; Takagishi, Hideyuki; Yamazaki, Ken; Shimoda, Tatsuya

    2016-04-20

    A polymeric precursor solution for semiconducting silicon called "liquid silicon" was synthesized and directly imprinted to form well-defined and fine amorphous silicon patterns. The spin-coated film was cured and imprinted followed by annealing at 380 °C to complete the polymer-to-silicon conversion. A pattern with dimensions of several hundreds of nanometers or less was obtained on a substrate. We demonstrated that the curing step before imprinting is particularly important in the imprinting process. A curing temperature of 140-180 °C was found to be optimal in terms of the film's deformability and molding properties. Fourier transform infrared spectroscopy and thermal analysis clarified that the cross-linking of the polymer due to the 1,2-hydrogen shift reaction was induced exponentially with the release of a large amount of SiH4/H2 gases at temperatures between 140 and 220 °C, leading to the solidification of the film. Consequently, the film completely lost its deformability at higher temperatures. Despite a volume shrinkage as large as 53-56% during the polymer-to-silicon conversion, well-defined angular patterns were preserved. Fine silicon patterns were formed via the direct imprinting of liquid silicon with high resolution and high throughput, demonstrating the usefulness of this technique for the future manufacturing of silicon electronics. PMID:27028558

  17. High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring.

    PubMed

    Barua, Subit; Kuizon, Salomon; Ted Brown, W; Junaid, Mohammed A

    2016-02-01

    Maternal nutrients play critical roles in modulating epigenetic events and exert long-term influences on the progeny's health. Folic acid (FA) supplementation during pregnancy has decreased the incidence of neural tube defects in newborns, but the influence of high doses of maternal FA supplementation on infants' brain development is unclear. The present study was aimed at investigating the effects of a high dose of gestational FA on the expression of genes in the cerebral hemispheres (CHs) of 1-day-old pups. One week prior to mating and throughout the entire period of gestation, female C57BL/6J mice were fed a diet, containing FA at either 2 mg/kg (control diet (CD)) or 20 mg/kg (high maternal folic acid (HMFA)). At postnatal day 1, pups from different dams were sacrificed and CH tissues were collected. Quantitative RT-PCR and Western blot analysis confirmed sex-specific alterations in the expression of several genes that modulate various cellular functions (P < 0.05) in pups from the HMFA group. Genomic DNA methylation analysis showed no difference in the level of overall methylation in pups from the HMFA group. These findings demonstrate that HMFA supplementation alters offsprings' CH gene expression in a sex-specific manner. These changes may influence infants' brain development. PMID:26547318

  18. Genomic imprinting and parent-of-origin effects on complex traits

    PubMed Central

    Lawson, Heather A.; Cheverud, James M.

    2014-01-01

    Parent-of-origin effects occur when the phenotypic effect of an allele depends on whether it is inherited from an individual’s mother or father. Several phenomena can cause parent-of-origin effects, with the best characterized being parent-of-origin dependent gene expression associated with genomic imprinting. Imprinting plays a critical role in a diversity of biological processes and in certain contexts it structures epigenetic relationships between DNA sequence and phenotypic variation. The development of new mapping approaches applied to the growing abundance of genomic data has demonstrated that imprinted genes can be important contributors to complex trait variation. Therefore, to understand the genetic architecture and evolution of complex traits, including complex diseases and traits of agricultural importance, it is crucial to account for these parent-of-origin effects. Here we discuss patterns of phenotypic variation associated with imprinting, evidence supporting its role in complex trait variation, and approaches for identifying its molecular signatures. PMID:23917626

  19. MicroRNAs 296 and 298 are imprinted and part of the GNAS/Gnas cluster and miR-296 targets IKBKE and Tmed9

    PubMed Central

    Robson, Joan E.; Eaton, Sally A.; Underhill, Peter; Williams, Debbie; Peters, Jo

    2012-01-01

    Genomic imprinting is the phenomenon whereby a subset of genes is differentially expressed according to parental origin. Imprinted genes tend to occur in clusters, and microRNAs are associated with the majority of well-defined clusters of imprinted genes. We show here that two microRNAs, miR-296 and miR-298, are part of the imprinted Gnas/GNAS clusters in both mice and humans. Both microRNAs show imprinted expression and are expressed from the paternally derived allele, but not the maternal allele. They arise from a long, noncoding antisense transcript, Nespas, with a promoter more than 27 kb away. Nespas had been shown previously to act in cis to regulate imprinted gene expression within the Gnas cluster. Using microarrays and luciferase assays, IKBKE, involved in many signaling pathways, and Tmed9, a protein transporter, were verified as new targets of miR-296. Thus, Nespas has two clear functions: as a cis-acting regulator within an imprinted gene cluster and as a precursor of microRNAs that modulate gene expression in trans. Furthermore, imprinted microRNAs, including miR-296 and miR-298, impose a parental specific modulation of gene expression of their target genes. PMID:22114321

  20. Imprinting and recalling cortical ensembles.

    PubMed

    Carrillo-Reid, Luis; Yang, Weijian; Bando, Yuki; Peterka, Darcy S; Yuste, Rafael

    2016-08-12

    Neuronal ensembles are coactive groups of neurons that may represent building blocks of cortical circuits. These ensembles could be formed by Hebbian plasticity, whereby synapses between coactive neurons are strengthened. Here we report that repetitive activation with two-photon optogenetics of neuronal populations from ensembles in the visual cortex of awake mice builds neuronal ensembles that recur spontaneously after being imprinted and do not disrupt preexisting ones. Moreover, imprinted ensembles can be recalled by single- cell stimulation and remain coactive on consecutive days. Our results demonstrate the persistent reconfiguration of cortical circuits by two-photon optogenetics into neuronal ensembles that can perform pattern completion. PMID:27516599

  1. Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

    PubMed

    Chen, Zhiyuan; Hagen, Darren E; Elsik, Christine G; Ji, Tieming; Morris, Collin James; Moon, Laura Emily; Rivera, Rocío Melissa

    2015-04-14

    Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day ∼105 Bos taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS. PMID:25825726

  2. Maternal Effects as the Cause of Parent-of-Origin Effects That Mimic Genomic Imprinting

    PubMed Central

    Hager, Reinmar; Cheverud, James M.; Wolf, Jason B.

    2008-01-01

    Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles. PMID:18245362

  3. Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting.

    PubMed

    Hager, Reinmar; Cheverud, James M; Wolf, Jason B

    2008-03-01

    Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles. PMID:18245362

  4. Recognition of Rhodobacter sphaeroides by microcontact-imprinted poly(ethylene-co-vinyl alcohol).

    PubMed

    Lee, Mei-Hwa; Thomas, James L; Li, Ming-Huan; Shih, Ching-Ping; Jan, Jeng-Shiung; Lin, Hung-Yin

    2015-11-01

    The immobilization of cells or microorganisms is important for bioseparations, in bioreactors producing cellular metabolites, and as receptors for biosensing. Cell-imprinted polymers (CIPs) have been shown to have cavities with complementary shapes and also high affinities for the template cells or microorganisms. However, the effects of binding to CIPs on gene expression are only beginning to be studied. In this work, the purple bacteria Rhodobacter sphaeroides was employed as a model for the imprinting of microorganisms. R. sphaeroides was first adsorbed on a glass slide as the stamp and then microcontact-imprinted onto poly(ethylene-co-vinyl alcohol), EVAL. The surfaces of the R. sphaeroides-imprinted (RsIPs) and non-imprinted (NIPs) EVAL thin films were examined by Raman spectrometry and scanning electron microscopy. The expression of the nitrogenase (nitrogen fixation, nifH) gene of R. sphaeroides adsorbed on both the RsIPs and NIPs EVAL thin films was also measured by the quantitative reverse transcription polymerase chain reaction (qRT-PCR); cells grown on imprinted polymer showed dramatic differences in gene expression compared to controls. PMID:26277714

  5. Xist imprinting is promoted by the hemizygous (unpaired) state in the male germ line

    PubMed Central

    Sun, Sha; Payer, Bernhard; Namekawa, Satoshi; An, Jee Young; Press, William; Catalan-Dibene, Jovani; Sunwoo, Hongjae; Lee, Jeannie T.

    2015-01-01

    The long noncoding X-inactivation–specific transcript (Xist gene) is responsible for mammalian X-chromosome dosage compensation between the sexes, the process by which one of the two X chromosomes is inactivated in the female soma. Xist is essential for both the random and imprinted forms of X-chromosome inactivation. In the imprinted form, Xist is paternally marked to be expressed in female embryos. To investigate the mechanism of Xist imprinting, we introduce Xist transgenes (Tg) into the male germ line. Although ectopic high-level Xist expression on autosomes can be compatible with viability, transgenic animals demonstrate reduced fitness, subfertility, defective meiotic pairing, and other germ-cell abnormalities. In the progeny, paternal-specific expression is recapitulated by the 200-kb Xist Tg. However, Xist imprinting occurs efficiently only when it is in an unpaired or unpartnered state during male meiosis. When transmitted from a hemizygous father (+/Tg), the Xist Tg demonstrates paternal-specific expression in the early embryo. When transmitted by a homozygous father (Tg/Tg), the Tg fails to show imprinted expression. Thus, Xist imprinting is directed by sequences within a 200-kb X-linked region, and the hemizygous (unpaired) state of the Xist region promotes its imprinting in the male germ line. PMID:26489649

  6. G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells

    PubMed Central

    Zhang, Tuo; Termanis, Ausma; Özkan, Burak; Bao, Xun X.; Culley, Jayne; de Lima Alves, Flavia; Rappsilber, Juri; Ramsahoye, Bernard; Stancheva, Irina

    2016-01-01

    Summary DNA methylation at imprinting control regions (ICRs) is established in gametes in a sex-specific manner and has to be stably maintained during development and in somatic cells to ensure the correct monoallelic expression of imprinted genes. In addition to DNA methylation, the ICRs are marked by allele-specific histone modifications. Whether these marks are essential for maintenance of genomic imprinting is largely unclear. Here, we show that the histone H3 lysine 9 methylases G9a and GLP are required for stable maintenance of imprinted DNA methylation in embryonic stem cells; however, their catalytic activity and the G9a/GLP-dependent H3K9me2 mark are completely dispensable for imprinting maintenance despite the genome-wide loss of non-imprinted DNA methylation in H3K9me2-depleted cells. We provide additional evidence that the G9a/GLP complex protects imprinted DNA methylation by recruitment of de novo DNA methyltransferases, which antagonize TET dioxygenass-dependent erosion of DNA methylation at ICRs. PMID:27052169

  7. Familiarity interferes with filial imprinting.

    PubMed

    van Kampen, H S; de Vos, G J

    1996-10-01

    The present study was performed to investigate whether and how pre-exposure to an object affects subsequent filial imprinting to that object. In Experiment 1 junglefowl chicks (Gallus gallus spadiceus) were first exposed to either a red object alone (control group), or a red and a yellow object simultaneously (experimental group; phase 1). Subsequently, all chicks were exposed to the yellow object in the presence of a black and blue one (phase 2). At the end of phase 1, most experimental chicks had developed a preference for the red object over the yellow one. At the end of phase 2, preferences of experimental chicks were shifted away from the yellow object towards the novel black and blue object, relative to preferences of control chicks. This shows that pre-exposure may interfere with imprinting. Experiment 2 revealed that when control chicks were tested with the yellow object at the end of phase 1, filial responses were as strong as in experimental chicks. This shows that the yellow object had not acquired control over filial behaviour during phase 1, and also that the relatively impaired imprinting on that object in phase 2 was not due to reduced generalization from the red object. One possible explanation why pre-exposure may interfere with imprinting is that familiarity alters the level of attention attracted by an object, a mechanism suggested to underlie 'latent inhibition' in conditioning. PMID:24897630

  8. Imprinted Polymers in Wastewater Treatment

    SciTech Connect

    Eastman, Christopher; Goodrich, Scott; Gartner, Isabelle; Mueller, Anja

    2004-03-31

    In wastewater treatment, a method that specifically recognizes a variety of impurities in a flexible manner would be useful for treatment facilities with varying needs. Current purification techniques (i.e. bacteria, oxidation, reduction, precipitation and filtration) are nonspecific and difficult to control in complex mixtures. Heavy metal removal is particularly important in improving the efficiency of wastewater treatment, as they inhibit or even destroy the bacteria used for filtration. Imprinting polymerization is a technique that allows for the efficient removal of specific compounds and has been used in purification of enantiomers. It has potential to be applied in wastewater systems with the impurities acting as the template for the imprinting polymerization. The polymer with the bound impurities intact can then be removed via precipitation. After removal of the impurity the polymer can be reused. Data for the imprinting polymerization of polyacrylates and polyacrylamides for several metal complexes will be presented. Imprinting polymerization in combination with emulsion polymerization to improve the removal of hydrophobic contaminants will be described. Removal efficiencies will be presented and compared with conventional wastewater treatment methods.

  9. Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.

    PubMed

    Chacón-Camacho, Oscar F; Sobreira, Nara; You, Jing; Piña-Aguilar, Raul E; Villegas-Ruiz, Vanessa; Zenteno, Juan C

    2016-07-01

    Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc. PMID:27139419

  10. Imprint Reduction with Shaped Pulses

    NASA Astrophysics Data System (ADS)

    Collins, T. J. B.; Skupsky, S.

    2000-10-01

    A novel technique for reducing laser imprint in OMEGA cryogenic targets has been developed. Standard ICF cryogenic targets consist of a shell of DT ice with a thin outer layer of CH. The presence of the CH layer gives rise to a brief period of early-time growth by the Rayleigh-Taylor (RT) instability, which effectively increases the amount of laser imprint by about a factor of 2. Two-dimensional ORCHID simulations show that by introducing a short, high-intensity spike at the start of the implosion, this early-time growth can be significantly reduced with only a small change to the calculated 1-D neutron yield. This work was supported by the U.S. Department of Energy Office of Inertial Confinement Fusion under Cooperative Agreement No. DE-FC03-92SF19460.

  11. Laser imprint studies on Nike

    NASA Astrophysics Data System (ADS)

    Pawley, C. J.; Obenschain, S. P.; Schmitt, A. J.; Colombant, D.; Gardner, J. H.; Fyfe, D. E.; Aglitskiy, Y.; Chan, Y.; Deniz, A. V.

    2000-10-01

    The very uniform Nike laser drive is being used to measure laser imprint on cryogenic and non-cryogenic targets. New 3-d simulations are compared with experimental R-T growth images for the standard Nike cryo-target as well as plastic targets with a variety of surface conditions. The standard Nike cryo-target is 180 μm of RF foam (density 50 mg/cc) mounted on 1.5 μm of improved Kapton. Targets have also been manufactured with 20, 30, and 60 μm wavelength sine waves cast into the Kapton to provide an initial perturbation. Liquid deuterium is wicked up into the foam just before the laser drive. These cryo-targets are similar to the ablator portion of the direct drive pellet design for NIF. Competition between laser imprint and pre-imposed modes is measured in both cryogenic and plastic targets. The results are compared to simulations.

  12. Rapid Birth-and-Death Evolution of Imprinted snoRNAs in the Prader-Willi Syndrome Locus: Implications for Neural Development in Euarchontoglires

    PubMed Central

    Zhang, Yi-Jun; Yang, Jian-Hua; Shi, Qiao-Su; Zheng, Ling-Ling; Liu, Jun; Zhou, Hui; Zhang, Hui; Qu, Liang-Hu

    2014-01-01

    Imprinted small nucleolar RNAs (snoRNAs) are only found in eutherian genomes and closely related to brain functions. A complex human neurological disease, Prader-Willi syndrome (PWS), is primarily attributed to the deletion of imprinted snoRNAs in chromosome 15q11-q13. Here we investigated the snoRNA repertoires in the PWS locus of 12 mammalian genomes and their evolution processes. A total of 613 imprinted snoRNAs were identified in the PWS homologous loci and the gene number was highly variable across lineages, with a peak in Euarchontoglires. Lineage-specific gene gain and loss events account for most extant genes of the HBII-52 (SNORD115) and the HBII-85 (SNORD116) gene family, and remarkable high gene-birth rates were observed in the primates and the rodents. Meanwhile, rapid sequence substitution occurred only in imprinted snoRNA genes, rather than their flanking sequences or the protein-coding genes located in the same imprinted locus. Strong selective constraints on the functional elements of these imprinted snoRNAs further suggest that they are subjected to birth-and-death evolution. Our data suggest that the regulatory role of HBII-52 on 5-HT2CR pre-mRNA might originate in the Euarchontoglires through adaptive process. We propose that the rapid evolution of PWS-related imprinted snoRNAs has contributed to the neural development of Euarchontoglires. PMID:24945811

  13. A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting.

    PubMed

    Weinberg, C R; Wilcox, A J; Lie, R T

    1998-04-01

    We describe a log-linear method for analysis of case-parent-triad data, based on maximum likelihood with stratification on parental mating type. The method leads to estimates of association parameters, such as relative risks, for a single allele, and also to likelihood ratio chi2 tests (LRTs) of linkage disequilibrium. Hardy-Weinberg equilibrium need not be assumed. Our simulations suggest that the LRT has power similar to that of the chi2 "score" test proposed by Schaid and Sommer and that both can outperform the transmission/disequilibrium test (TDT), although the TDT can perform better under an additive model of inheritance. Because a restricted version of the LRT is asymptotically equivalent to the TDT, the proposed test can be regarded as a generalization of the TDT. The method that we describe generalizes easily to accommodate maternal effects on risk and, in fact, produces powerful and orthogonal tests of the contribution of fetal versus maternal genetic factors. We further generalize the model to allow for effects of parental imprinting. Imprinting effects can be fitted by a simple, iterative procedure that relies on the expectation-maximization algorithm and that uses standard statistical software for the maximization steps. Simulations reveal that LRT tests for detection of imprinting have very good operating characteristics. When a single allele is under study, the proposed method can yield powerful tests for detection of linkage disequilibrium and is applicable to a broader array of causal scenarios than is the TDT. PMID:9529360

  14. Negative energy balance affects imprint stability in oocytes recovered from postpartum dairy cows.

    PubMed

    O'Doherty, Alan M; O'Gorman, Aoife; al Naib, Abdullah; Brennan, Lorraine; Daly, Edward; Duffy, Pat; Fair, Trudee

    2014-09-01

    Ovarian follicle development in post-partum, high-producing dairy cows, occurs in a compromised endogenous metabolic environment (referred to as negative energy balance, NEB). Key events that occur during oocyte/follicle growth, such as the vital process of genomic imprinting, may be detrimentally affected by this altered ovarian environment. Imprinting is crucial for placental function and regulation of fetal growth, therefore failure to establish and maintain imprints during oocyte growth may contribute to early embryonic loss. Using ovum pick-up (OPU), oocytes and follicular fluid samples were recovered from cows between days 20 and 115 post-calving, encompassing the NEB period. In a complimentary study, cumulus oocyte complexes were in vitro matured under high non-esterified fatty acid (NEFA) concentrations and in the presence of the methyl-donor S-adenosylmethionine (SAM). Pyrosequencing revealed the loss of methylation at several imprinted loci in the OPU derived oocytes. The loss of DNA methylation was observed at the PLAGL1 locus in oocytes, following in vitro maturation (IVM) in the presence of elevated NEFAs and SAM. Finally, metabolomic analysis of postpartum follicular fluid samples revealed significant differences in several branched chain amino acids, with fatty acid profiles bearing similarities to those characteristic of lactating dairy cows. These results provide the first evidence that (1) the postpartum ovarian environment may affect maternal imprint acquisition and (2) elevated NEFAs during IVM can lead to the loss of imprinted gene methylation in bovine oocytes. PMID:25084396

  15. Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice

    PubMed Central

    Lassi, Glenda; Ball, Simon T.; Maggi, Silvia; Colonna, Giovanni; Nieus, Thierry; Cero, Cheryl; Bartolomucci, Alessandro; Peters, Jo; Tucci, Valter

    2012-01-01

    It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes. PMID:22589743

  16. Identification of the control region for tissue-specific imprinting of the stimulatory G protein α-subunit

    PubMed Central

    Liu, Jie; Chen, Min; Deng, Chuxia; Bourc'his, Déborah; Nealon, Julie G.; Erlichman, Beth; Bestor, Timothy H.; Weinstein, Lee S.

    2005-01-01

    Gnas is a complex gene with multiple imprinted promoters. The upstream Nesp and Nespas/Gnasxl promoters are paternally and maternally methylated, respectively. The downstream promoter for the stimulatory G protein α-subunit (Gsα) is unmethylated, although in some tissues (e.g., renal proximal tubules), Gsα is poorly expressed from the paternal allele. Just upstream of the Gsα promoter is a primary imprint mark (1A region) where maternal-specific methylation is established during oogenesis. Pseudohypoparathyroidism type 1B, a disorder of renal parathyroid hormone resistance, is associated with loss of 1A methylation. Analysis of embryos of Dnmt3L–/– mothers (which cannot methylate maternal imprint marks) showed that Nesp, Nespas/Gnasxl, and 1A imprinting depend on one or more maternal primary imprint marks. We generated mice with deletion of the 1A differentially methylated region. These mice had normal Nesp-Nespas/Gnasxl imprinting, indicating that the Gnas locus contains two independent imprinting domains (Nespas-Nespas/Gnasxl and 1A-Gsα) controlled by distinct maternal primary imprint marks. Paternal, but not maternal, 1A deletion resulted in Gsα overexpression in proximal tubules and evidence for increased parathyroid hormone sensitivity but had no effect on Gsα expression in other tissues where Gsα is normally not imprinted. The 1A region is a maternal imprint mark that contains one or more methylation-sensitive cis-acting elements that suppress Gsα expression from the paternal allele in a tissue-specific manner. PMID:15811946

  17. Distributed feedback imprinted electrospun fiber lasers.

    PubMed

    Persano, Luana; Camposeo, Andrea; Del Carro, Pompilio; Fasano, Vito; Moffa, Maria; Manco, Rita; D'Agostino, Stefania; Pisignano, Dario

    2014-10-01

    Imprinted, distributed feedback lasers are demonstrated on individual, active electrospun polymer nanofibers. In addition to advantages related to miniaturization, optical confinement and grating nanopatterning lead to a significant threshold reduction compared to conventional thin-film lasers. The possibility of imprinting arbitrary photonic crystal geometries on electrospun lasing nanofibers opens new opportunities for realizing optical circuits and chips. PMID:25042888

  18. Mitigation of initial imprinting with diamond ablator

    NASA Astrophysics Data System (ADS)

    Kato, Hiroki; Shigemori, Keisuke; Hironaka, Youichirou; Terasaki, Hidenori; Sakaiya, Tatsuhiro; Hosogi, Ryouta; Nakai, Mitsuo; Azechi, Hiroshi

    2014-10-01

    In direct drive inertial confinement fusion, where laser light directly irradiates the target, surface perturbations on the target are seeded by initial imprint due to laser irradiation nonuniformity. It is the initial imprint that become the seed of the hydrodynamic instability, and decisive solutions for the mitigation of initial imprinting is required. We focused on material stiffness of ablator as an idea that was effective for mitigation of imprinting and adopted the diamond with low compressibility as an ablator material. In the imprint experiments, the diamond foils were irradiated with a foot pulse at an intensity of ~ 4.0 × 1012W/cm2 with 1.3 ns width, on which a stationary spatial nonuniformity with sinusoidal shape of 100 μm wavelength was imposed by implementing a grid mask. The foils were subsequently accelerated by a uniform main laser pulse of ~ 1.0 × 1014 W/cm2 and imprinted perturbation were observed to be amplified by Rayleigh-Taylor instability through face-on x-ray backlight measurements. We deduced the equivalent initial surface roughness for the imprinted foil. We verified the mitigation of initial imprinting with diamond from the quantitative evaluation.

  19. Astrobiological Molecularly Imprinted Polymer Sensors

    NASA Astrophysics Data System (ADS)

    Izenberg, N. R.; Murray, G. M.; van Houten, K. A.; Hofstra, A. A.

    2005-12-01

    Development of Molecularly Imprinted Polymer (MIP) sensors for astrobiology is intended to provide a new class of microlaboratory sensors compatible with other life or biomarker detection. Molecular imprinting is a process for making selective binding sites in synthetic polymers. The process may be approached by designing the recognition site or by simply choosing monomers that may have favorable interactions with the imprinting molecule. We are working to apply this methodology to astrobiology for development of a reliable, low cost, low mass, low power consumption sensor technology for quantitative in-situ analysis of biochemistry, biomarkers, and other indicators of astrobiological importance. Specific goals of the project are: 1) To develop a general methodology and specific methods for MIP-based sensor construction. The overall methodology will guide procedures for design and testing of any desired sensor. Specific methods will be applied to key families and specific species of astrobiological interest, i.e., alkanes (and Polycyclic aromatic hydrocarbons - PAHs), amino acids, steroids, and hopanes; 2) To construct and characterize the general family and specific species sensors. We will test for accuracy, precision, interferences, and limitations of the sensor against blanks, standards, and known terrestrial biological environment samples. Additional testing will determine sturdiness and longevity of sensors after exposure to transit conditions (launch and space environment), and at potential target environments (pressure, temperature, pH, etc.); and 3) To construct and demonstrate the combination of multiple sensors into a viable prototype instrument, and roadmap the expansion of potential instrument capabilities and exploration of the ultimate environmental limitations of the technology, and the necessary changes and additions to create a mission-ready instrument. Initial work has resulted successful detection of aqueous alanine (D and L) with simple MIP

  20. No Evidence for Enrichment in Schizophrenia for Common Allelic Associations at Imprinted Loci

    PubMed Central

    Escott-Price, Valentina; Kirov, George; Rees, Elliott; Isles, Anthony R.; Owen, Michael J.; O’Donovan, Michael C.

    2015-01-01

    Most genetic studies assume that the function of a genetic variant is independent of the parent from which it is inherited, but this is not always true. The best known example of parent-of-origin effects arises with respect to alleles at imprinted loci. In classical imprinting, characteristically, either the maternal or paternal copy is expressed, but not both. Only alleles present in one of the parental copies of the gene, the expressed copy, is likely to contribute to disease. It has been postulated that imprinting is important in central nervous system development, and that consequently, imprinted loci may be involved in schizophrenia. If this is true, allowing for parent-of-origin effects might be important in genetic studies of schizophrenia. Here, we use genome-wide association data from one of the world’s largest samples (N = 695) of parent schizophrenia-offspring trios to test for parent-of-origin effects. To maximise power, we restricted our analyses to test two main hypotheses. If imprinting plays a disproportionate role in schizophrenia susceptibility, we postulated a) that alleles showing robust evidence for association to schizophrenia from previous genome-wide association studies should be enriched for parent-of-origin effects and b) that genes at loci imprinted in humans or mice should be enriched both for genome-wide significant associations, and in our sample, for parent-of-origin effects. Neither prediction was supported in the present study. We have shown, that it is unlikely that parent-of-origin effects or imprinting play particularly important roles in schizophrenia, although our findings do not exclude such effects at specific loci nor do they exclude such effects among rare alleles. PMID:26633303

  1. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment

    PubMed Central

    Court, Franck; Tayama, Chiharu; Romanelli, Valeria; Martin-Trujillo, Alex; Iglesias-Platas, Isabel; Okamura, Kohji; Sugahara, Naoko; Simón, Carlos; Moore, Harry; Harness, Julie V.; Keirstead, Hans; Sanchez-Mut, Jose Vicente; Kaneki, Eisuke; Lapunzina, Pablo; Soejima, Hidenobu; Wake, Norio; Esteller, Manel; Ogata, Tsutomu; Hata, Kenichiro; Nakabayashi, Kazuhiko; Monk, David

    2014-01-01

    Differential methylation between the two alleles of a gene has been observed in imprinted regions, where the methylation of one allele occurs on a parent-of-origin basis, the inactive X-chromosome in females, and at those loci whose methylation is driven by genetic variants. We have extensively characterized imprinted methylation in a substantial range of normal human tissues, reciprocal genome-wide uniparental disomies, and hydatidiform moles, using a combination of whole-genome bisulfite sequencing and high-density methylation microarrays. This approach allowed us to define methylation profiles at known imprinted domains at base-pair resolution, as well as to identify 21 novel loci harboring parent-of-origin methylation, 15 of which are restricted to the placenta. We observe that the extent of imprinted differentially methylated regions (DMRs) is extremely similar between tissues, with the exception of the placenta. This extra-embryonic tissue often adopts a different methylation profile compared to somatic tissues. Further, we profiled all imprinted DMRs in sperm and embryonic stem cells derived from parthenogenetically activated oocytes, individual blastomeres, and blastocysts, in order to identify primary DMRs and reveal the extent of reprogramming during preimplantation development. Intriguingly, we find that in contrast to ubiquitous imprints, the majority of placenta-specific imprinted DMRs are unmethylated in sperm and all human embryonic stem cells. Therefore, placental-specific imprinting provides evidence for an inheritable epigenetic state that is independent of DNA methylation and the existence of a novel imprinting mechanism at these loci. PMID:24402520

  2. Transcription and imprinting dynamics in developing postnatal male germline stem cells

    PubMed Central

    Hammoud, Saher Sue; Low, Diana H.P.; Yi, Chongil; Lee, Chee Leng; Oatley, Jon M.; Payne, Christopher J.; Carrell, Douglas T.; Guccione, Ernesto; Cairns, Bradley R.

    2015-01-01

    Postnatal spermatogonial stem cells (SSCs) progress through proliferative and developmental stages to populate the testicular niche prior to productive spermatogenesis. To better understand, we conducted extensive genomic profiling at multiple postnatal stages on subpopulations enriched for particular markers (THY1, KIT, OCT4, ID4, or GFRa1). Overall, our profiles suggest three broad populations of spermatogonia in juveniles: (1) epithelial-like spermatogonia (THY1+; high OCT4, ID4, and GFRa1), (2) more abundant mesenchymal-like spermatogonia (THY1+; moderate OCT4 and ID4; high mesenchymal markers), and (3) (in older juveniles) abundant spermatogonia committing to gametogenesis (high KIT+). Epithelial-like spermatogonia displayed the expected imprinting patterns, but, surprisingly, mesenchymal-like spermatogonia lacked imprinting specifically at paternally imprinted loci but fully restored imprinting prior to puberty. Furthermore, mesenchymal-like spermatogonia also displayed developmentally linked DNA demethylation at meiotic genes and also at certain monoallelic neural genes (e.g., protocadherins and olfactory receptors). We also reveal novel candidate receptor–ligand networks involving SSCs and the developing niche. Taken together, neonates/juveniles contain heterogeneous epithelial-like or mesenchymal-like spermatogonial populations, with the latter displaying extensive DNA methylation/chromatin dynamics. We speculate that this plasticity helps SSCs proliferate and migrate within the developing seminiferous tubule, with proper niche interaction and membrane attachment reverting mesenchymal-like spermatogonial subtype cells back to an epithelial-like state with normal imprinting profiles. PMID:26545815

  3. Imprinting mutations suggested by abnormal DNA methylation patterns in familial angelman and Prader-Willi syndromes

    SciTech Connect

    Reis, A. ); Dittrich, B.; Buiting, K.; Gillessen-Kaesbach, G.; Horsthemke, B. ); Greger, V.; Lalande, M. ); Anvret, M. )

    1994-05-01

    The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation. The authors have found two Prader-Willi syndrome families in which the patients carry a maternal methylation imprint on the paternal chromosome. In one of these families, the patients have a small deletion encompassing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, they have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelman syndrome patients who carry a paternal methylation imprint on the maternal chromosome. These Angelman and Prader-Willi syndrome patients may have a defect in the imprinting process in 15q11-13. The authors propose a model in which a cis-acting mutation prevents the resetting of the imprinting signal in the germ line and thus disturbs the expression of imprinted genes in this region. 39 refs., 4 figs., 1 tab.

  4. Transcription and imprinting dynamics in developing postnatal male germline stem cells.

    PubMed

    Hammoud, Saher Sue; Low, Diana H P; Yi, Chongil; Lee, Chee Leng; Oatley, Jon M; Payne, Christopher J; Carrell, Douglas T; Guccione, Ernesto; Cairns, Bradley R

    2015-11-01

    Postnatal spermatogonial stem cells (SSCs) progress through proliferative and developmental stages to populate the testicular niche prior to productive spermatogenesis. To better understand, we conducted extensive genomic profiling at multiple postnatal stages on subpopulations enriched for particular markers (THY1, KIT, OCT4, ID4, or GFRa1). Overall, our profiles suggest three broad populations of spermatogonia in juveniles: (1) epithelial-like spermatogonia (THY1(+); high OCT4, ID4, and GFRa1), (2) more abundant mesenchymal-like spermatogonia (THY1(+); moderate OCT4 and ID4; high mesenchymal markers), and (3) (in older juveniles) abundant spermatogonia committing to gametogenesis (high KIT(+)). Epithelial-like spermatogonia displayed the expected imprinting patterns, but, surprisingly, mesenchymal-like spermatogonia lacked imprinting specifically at paternally imprinted loci but fully restored imprinting prior to puberty. Furthermore, mesenchymal-like spermatogonia also displayed developmentally linked DNA demethylation at meiotic genes and also at certain monoallelic neural genes (e.g., protocadherins and olfactory receptors). We also reveal novel candidate receptor-ligand networks involving SSCs and the developing niche. Taken together, neonates/juveniles contain heterogeneous epithelial-like or mesenchymal-like spermatogonial populations, with the latter displaying extensive DNA methylation/chromatin dynamics. We speculate that this plasticity helps SSCs proliferate and migrate within the developing seminiferous tubule, with proper niche interaction and membrane attachment reverting mesenchymal-like spermatogonial subtype cells back to an epithelial-like state with normal imprinting profiles. PMID:26545815

  5. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes.

    PubMed

    Court, Franck; Martin-Trujillo, Alex; Romanelli, Valeria; Garin, Intza; Iglesias-Platas, Isabel; Salafsky, Ira; Guitart, Miriam; Perez de Nanclares, Guiomar; Lapunzina, Pablo; Monk, David

    2013-04-01

    Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance. PMID:23335487

  6. Imprinted polymer sensors for contamination detection

    NASA Astrophysics Data System (ADS)

    Murray, George M.; Arnold, Bradley R.; Kelly, Craig A.; Uy, O. Manuel

    2001-03-01

    Molecular imprinting is a useful technique for making a chemically selective binding site. The method involves building a synthetic polymeric scaffold of molecular complements containing the target molecule with subsequent removal of the target to leave a cavity with a structural "memory" of the target. Molecularly imprinted polymers can be employed as selective adsorbents of specific molecules or molecular functional groups. The imprinted polymers can be fashioned into membranes that can be used to form ion selective electrodes for an imprinted ion. By incorporating molecules or metal ions with useful optical properties in the binding sites of imprinted polymers, spectroscopic sensors for the imprinted molecule may be made. A variety of metal ion selective electrodes and a Pb2+ ion optrode based on imprinted polymers have been fabricated and tested.1-4 Additionally, a sensor for the hydrolysis product of the nerve agent Soman has been developed using a luminescent lanthanide ion, Eu(III), as optical transducer.5 Our research continues to explore other means to employ electrochemical and optical transduction.

  7. Ferroelectric capacitor with reduced imprint

    DOEpatents

    Evans, Jr., Joseph T.; Warren, William L.; Tuttle, Bruce A.; Dimos, Duane B.; Pike, Gordon E.

    1997-01-01

    An improved ferroelectric capacitor exhibiting reduced imprint effects in comparison to prior art capacitors. A capacitor according to the present invention includes top and bottom electrodes and a ferroelectric layer sandwiched between the top and bottom electrodes, the ferroelectric layer comprising a perovskite structure of the chemical composition ABO.sub.3 wherein the B-site comprises first and second elements and a dopant element that has an oxidation state greater than +4. The concentration of the dopant is sufficient to reduce shifts in the coercive voltage of the capacitor with time. In the preferred embodiment of the present invention, the ferroelectric element comprises Pb in the A-site, and the first and second elements are Zr and Ti, respectively. The preferred dopant is chosen from the group consisting of Niobium, Tantalum, and Tungsten. In the preferred embodiment of the present invention, the dopant occupies between 1 and 8% of the B-sites.

  8. A Bayesian Method for Simultaneously Detecting Mendelian and Imprinted Quantitative Trait Loci in Experimental Crosses of Outbred Species

    PubMed Central

    Hayashi, Takeshi; Awata, Takashi

    2008-01-01

    Genomic imprinting is interpreted as a phenomenon, in which some genes inherited from one parent are not completely expressed due to modification of the genome caused during gametogenesis. Subsequently, the expression level of an allele at the imprinted gene is changed dependent on the parental origin, which is referred to as the parent-of-origin effect. In livestock, some QTL for reproductive performance and meat productivity have been reported to be imprinted. So far, methods detecting imprinted QTL have been proposed on the basis of interval mapping, where only a single QTL was tested at a time. In this study, we developed a Bayesian method for simultaneously mapping multiple QTL, allowing the inference about expression modes of QTL in an outbred F2 family. The inference about whether a QTL is Mendelian or imprinted was made using Markov chain Monte Carlo estimation by comparing the goodness-of-fits between models, assuming the presence and the absence of parent-of-origin effect at a QTL. We showed by the analyses of simulated data sets that the Bayesian method can effectively detect both Mendelian QTL and imprinted QTL. PMID:18202392

  9. Influence of mom and dad: quantitative genetic models for maternal effects and genomic imprinting.

    PubMed

    Santure, Anna W; Spencer, Hamish G

    2006-08-01

    The expression of an imprinted gene is dependent on the sex of the parent it was inherited from, and as a result reciprocal heterozygotes may display different phenotypes. In contrast, maternal genetic terms arise when the phenotype of an offspring is influenced by the phenotype of its mother beyond the direct inheritance of alleles. Both maternal effects and imprinting may contribute to resemblance between offspring of the same mother. We demonstrate that two standard quantitative genetic models for deriving breeding values, population variances and covariances between relatives, are not equivalent when maternal genetic effects and imprinting are acting. Maternal and imprinting effects introduce both sex-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the two approaches. We use a simple example to demonstrate that both imprinting and maternal genetic effects add extra terms to covariances between relatives and that model misspecification may over- or underestimate true covariances or lead to extremely variable parameter estimation. Thus, an understanding of various forms of parental effects is essential in correctly estimating quantitative genetic variance components. PMID:16751674

  10. A Micro-Silicon Chip for in Vivo Cerebral Imprint in Monkey

    PubMed Central

    2012-01-01

    Access to cerebral tissue is essential to better understand the molecular mechanisms associated with neurodegenerative diseases. In this study, we present, for the first time, a new tool designed to obtain molecular and cellular cerebral imprints in the striatum of anesthetized monkeys. The imprint is obtained during a spatially controlled interaction of a chemically modified micro-silicon chip with the brain tissue. Scanning electron and immunofluorescence microscopies showed homogeneous capture of cerebral tissue. Nano-liquid chromatography–tandem mass spectrometry (nano-LC-MS/MS) analysis of proteins harvested on the chip allowed the identification of 1158 different species of proteins. The gene expression profiles of mRNA extracted from the imprint tool showed great similarity to those obtained via the gold standard approach, which is based on post-mortem sections of the same nucleus. Functional analysis of the harvested molecules confirmed the spatially controlled capture of striatal proteins implicated in dopaminergic regulation. Finally, the behavioral monitoring and histological results establish the safety of obtaining repeated cerebral imprints in striatal regions. These results demonstrate the ability of our imprint tool to explore the molecular content of deep brain regions in vivo. They open the way to the molecular exploration of brain in animal models of neurological diseases and will provide complementary information to current data mainly restricted to post-mortem samples. PMID:23509975