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1

Aberrant Gene Expression in Humans  

PubMed Central

Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions. PMID:25617623

Yang, Ence; Ji, Guoli; Brinkmeyer-Langford, Candice L.; Cai, James J.

2015-01-01

2

Aberrant Epigenetic Silencing Is Triggered by a Transient Reduction in Gene Expression  

Microsoft Academic Search

BackgroundAberrant epigenetic silencing plays a major role in cancer formation by inactivating tumor suppressor genes. While the endpoints of aberrant silencing are known, i.e., promoter region DNA methylation and altered histone modifications, the triggers of silencing are not known. We used the tet-off system to test the hypothesis that a transient reduction in gene expression will sensitize a promoter to

Jon A. Oyer; Adrian Chu; Sukhmani Brar; Mitchell S. Turker; Michael Freitag

2009-01-01

3

[Aberrant expression of sox2 gene in malignant gliomas].  

PubMed

Both genetic and epigenetic changes underlite the mechanisms of tumor initiation and progression. In the present study we analyze sox2 gene expression and its epigenetic regulation in primary cultures of malignant gliomas. The sox2 expression was detected in the vast majority (74%) of the investigated gliomas and absent in morphologically normal brain tissue. This indicates the process of glioma malignant transformation. We have also shown that the association of different areas of the sox2 gene with important epigenetic markers, posttranslational modifications of H3 histone H3K4ac and H3K9met3, does not correlate with the sox2 expression. However, this may indicate the stochastic nature of the regulation of sox2 gene expression in malignant gliomas. PMID:25696994

Volnitski?, A V; Semenova, E V; Shtam, T A; Kovalev, R A; Filatov, M V

2014-01-01

4

Aberrant Gene Expression in Dogs with Portosystemic Shunts  

PubMed Central

Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in IHPSS and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy. PMID:23451256

Grinwis, Guy C. M.; Kummeling, Anne; van Gils, Ingrid H. M.; Koerkamp, Marian J. A. Groot.; van Leenen, Dik; Holstege, Frank C. P.; Penning, Louis C.; Rothuizen, Jan; Leegwater, Peter A. J.; Spee, Bart

2013-01-01

5

Aberrant epigenetic changes and gene expression in cloned cattle dying around birth  

Microsoft Academic Search

BACKGROUND: Aberrant reprogramming of donor somatic cell nuclei may result in many severe problems in animal cloning. To assess the extent of abnormal epigenetic modifications and gene expression in clones, we simultaneously examined DNA methylation, histone H4 acetylation and expression of six genes (?-actin, VEGF, oct4, TERT, H19 and Igf2) and a repetitive sequence (art2) in five organs (heart, liver,

Li Lin; Qiang Li; Lei Zhang; Dingsheng Zhao; Yunping Dai; Ning Li

2008-01-01

6

From DNA Copy Number to Gene Expression: Local aberrations, Trisomies and Monosomies  

NASA Astrophysics Data System (ADS)

The goal of my PhD research was to study the effect of DNA copy number changes on gene expression. DNA copy number aberrations may be local, encompassing several genes, or on the level of an entire chromosome, such as trisomy and monosomy. The main dataset I studied was of Glioblastoma, obtained in the framework of a collaboration, but I worked also with public datasets of cancer and Down's Syndrome. The molecular basis of expression changes in Glioblastoma. Glioblastoma is the most common and aggressive type of primary brain tumors in adults. In collaboration with Prof. Hegi (CHUV, Switzerland), we analyzed a rich Glioblastoma dataset including clinical information, DNA copy number (array CGH) and expression profiles. We explored the correlation between DNA copy number and gene expression at the level of chromosomal arms and local genomic aberrations. We detected known amplification and over expression of oncogenes, as well as deletion and down-regulation of tumor suppressor genes. We exploited that information to map alterations of pathways that are known to be disrupted in Glioblastoma, and tried to characterize samples that have no known alteration in any of the studied pathways. Identifying local DNA aberrations of biological significance. Many types of tumors exhibit chromosomal losses or gains and local amplifications and deletions. A region that is aberrant in many tumors, or whose copy number change is stronger, is more likely to be clinically relevant, and not just a by-product of genetic instability. We developed a novel method that defines and prioritizes aberrations by formalizing these intuitions. The method scores each aberration by the fraction of patients harboring it, its length and its amplitude, and assesses the significance of the score by comparing it to a null distribution obtained by permutations. This approach detects genetic locations that are significantly aberrant, generating a 'genomic aberration profile' for each sample. The 'genomic aberration profile' is then combined with chromosomal arm status (gain/loss) to define a succinct genomic signature for each tumor. Unsupervised clustering of the samples based on these genomic signatures can reveal novel tumor subtypes. This approach was applied to datasets from three types of brain tumors: Glioblastoma, Medulloblastoma and Neuroblastoma, and identified a new subtype in Medulloblastoma, characterized by many chromosomal aberrations. Elucidating the transcriptional effect of monosomy and trisomy. Trisomy and monosomy are expected to impact the expression of genes that are located on the affected chromosome. Analysis of several cancer datasets revealed that not all the genes on the aberrant chromosome are affected by the change of copy number. Affected genes exhibit a wide range of expression changes with varying penetrance. Specifically, (1) The effect of trisomy is much more conserved among individuals than the effect of monosomy and (2) the expression level of a gene in the diploid is significantly correlated with the level of change between the diploid and the trisomy or monosomy.

Shay, Tal

7

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours  

PubMed Central

Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2?-deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5? region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5? CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours. PMID:15756280

Murai, M; Toyota, M; Satoh, A; Suzuki, H; Akino, K; Mita, H; Sasaki, Y; Ishida, T; Shen, L; Garcia-Manero, G; Issa, J-P J; Hinoda, Y; Tokino, T; Imai, K

2005-01-01

8

HOXA11 gene is hypermethylation and aberrant expression in gastric cancer  

PubMed Central

Background Aberrant DNA methylation is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes and other genes in diverse human cancers. Gastric carcinoma is one of the tumors with a high frequency of aberrant methylation in promoter region. Hence we investigated the promoter methylation status and expression level of HOXA11 gene which may involve in GC development. Methods Thirty-two surgical excised gastric cancer specimens, twelve paired adjacent non-cancerous specimens and seven normal gastric mucosas were examined. The methylation status and expression level of HOXA11 gene were determined by bisulfite sequencing polymerase chain reaction (BSP), real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) respectively. HOXA11 expression was knocked-down with siRNA to mimic HOXA11 gene hypermethylation and ability of cell proliferation and migration was determinate. In addition, we analyzed and correlated the findings with clinicopathological features. Results The methylation level of HOXA11 gene in gastric cancer tissues and adjacent non-cancerous tissues were higher than those in normal gastric mucosa (P < 0.05). The methylation level was higher in TNM III and IV patients of GC than those in TNM I and II patients (P < 0.05). The expression of HOXA11 mRNA and protein decreased in normal gastric mucosa, peri-cancer tissue and GC (P < 0.05). HOXA11 expression was inversely correlated with DNA methylation (P < 0.05). Knocked-down of HOXA11 expression with siRNA in BGC-823 cells enhanced cell proliferation compared with control, but no significant different was observed in migration ability. Conclusion Hypermethylation and decreased expression of HOXA11 gene may be involved in the carcinogenesis and development of GC and may provide useful information for the prediction of the malignant behaviors of GC. And the expression of HOXA11 is impaired by DNA methylation. However, repression of HOXA11 expression promoted BGC-823 cell proliferation.

2014-01-01

9

Redox-sensitive gene-regulatory events controlling aberrant matrix metalloproteinase-1 expression.  

PubMed

Aberrant matrix metalloproteinase-1 (MMP-1) expression contributes to the pathogenesis of many degenerative disease processes that are associated with increased oxidative damage or stress. We and others have established that shifts in steady-state H2O2 production resulting from enforced antioxidant gene expression, senescence, or UV irradiation control MMP-1 expression. Here we establish that histone deacetylase-2 (HDAC2) protein levels and its occupancy of the MMP-1 promoter are decreased in response to enforced manganese superoxide dismutase (Sod2) expression. Inhibition of HDAC activity further accentuates the redox-dependent expression of MMP-1. Sod2-dependent decreases in HDAC2 are associated with increases in a proteasome-sensitive pool of ubiquitinylated HDAC2 and MMP-1-specific histone H3 acetylation. Sod2 overexpression also enhanced recruitment of Ets-1, c-Jun, c-Fos, and the histone acetyltransferase PCAF to the distal and proximal regions of the MMP-1 promoter. Furthermore, the Sod2-dependent expression of MMP-1 can be reversed by silencing the transcriptional activator c-Jun. All of the above Sod2-dependent alterations are largely reversed by catalase coexpression, indicating that the redox control of MMP-1 is H2O2-dependent. These findings identify a novel redox regulation of MMP-1 transcription that involves site-specific promoter recruitment of both activating factors and chromatin-modifying enzymes, which converge to maximally drive MMP-1 gene expression. PMID:24973648

Bartling, Toni R; Subbaram, Sita; Clark, Ryan R; Chandrasekaran, Akshaya; Kar, Supriya; Melendez, J Andres

2014-09-01

10

Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene?expression  

PubMed Central

Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming S-adenosyl-methionine (SAM) in the process. The fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis. Here we test the hypothesis that arsenic-induced initiation results from DNA hypomethylation caused by continuous methyl depletion. The hypothesis was tested by first inducing transformation in a rat liver epithelial cell line by chronic exposure to low levels of arsenic, as confirmed by the development of highly aggressive, malignant tumors after inoculation of cells into Nude mice. Global DNA hypomethylation occurred concurrently with malignant transformation and in the presence of depressed levels of S-adenosyl-methionine. Arsenic-induced DNA hypomethylation was a function of dose and exposure duration, and remained constant even after withdrawal of arsenic. Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells. Acute arsenic or arsenic at nontransforming levels did not induce global hypomethylation of DNA. Whereas transcription of DNA MeTase was elevated, the MeTase enzymatic activity was reduced with arsenic transformation. Taken together, these results indicate arsenic can act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression, and they constitute a tenable theory of mechanism in arsenic carcinogenesis. PMID:9380733

Zhao, Christopher Q.; Young, Matthew R.; Diwan, Bhalchandra A.; Coogan, Timothy P.; Waalkes, Michael P.

1997-01-01

11

Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic  

PubMed Central

Our prior work showed that brief exposure of pregnant C3H mice to inorganic arsenic-induced hepatocellular carcinoma (HCC) formation in adult male offspring. The current study examined the early hepatic events associated with this oncogenic transformation. Pregnant mice were exposed to a known carcinogenic dose of arsenic (85 ppm) in the drinking water from gestation days 8 to 18. The dams were allowed to give birth and liver samples from newborn males were analyzed for arsenic content, global DNA methylation and aberrant expression of genes relevant to the carcinogenic process. Arsenic content in newborn liver reached 57 ng/g wet weight, indicating arsenic had crossed the placenta, reached the fetal liver and that significant amounts remained after birth. Global methylation status of hepatic DNA was not altered by arsenic in the newborn. However, a significant reduction in methylation occurred globally in GC-rich regions. Microarray and real-time RT-PCR analysis showed that arsenic exposure enhanced expression of genes encoding for glutathione production and caused aberrant expression of genes related to insulin growth factor signaling pathways and cytochrome P450 enzymes. Other expression alterations observed in the arsenic-treated male mouse newborn liver included the overexpression of cdk-inhibitors and stress response genes including increased expression of metallothionein-1 and decreased expression of betaine-homocysteine methyltransferase and thioether S-methyltransferase. Thus, transplacental exposure to arsenic at a hepatocarcinogenic dose induces alterations in DNA methylation and a complex set of aberrant gene expressions in the newborn liver, a target of arsenic carcinogenesis. PMID:17451858

Xie, Yaxiong; Liu, Jie; Benbrahim-Tallaa, Lamia; Ward, Jerry M.; Logsdon, Daniel; Diwan, Bhalchandra A.; Waalkes, Michael P.

2008-01-01

12

Aberrant expression of the CHFR prophase checkpoint gene in human B-cell non-Hodgkin lymphoma.  

PubMed

Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis, which has become an interesting target for understanding cancer pathogenesis. Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. In the present study, we examined the expression of CHFR in B-cell non-Hodgkin lymphoma (B-NHL) in vitro and in vivo. Our results showed that the expression level of CHFR mRNA and protein was reduced in B-NHL tissue samples and B cell lines. Furthermore, CHFR methylation was detected in 39 of 122 B-NHL patients, which was not found in noncancerous reactive hyperplasia of lymph node (RH) tissues. CHFR methylation correlated with the reduced expression of CHFR, high International Prognostic Index (IPI) scores and later pathologic Ann Arbor stages of B-NHL. Treatment with demethylation reagent, 5-Aza-dC, could eliminate the hypermethylation of CHFR, enhance CHFR expression and cell apoptosis and inhibit the cell proliferation of Raji cells, which could be induced by high expression of CHFR in Raji cells. Our results indicated that aberrant methylation of CHFR may be associated with the pathogenesis, progression for B-NHL, which might be a novel molecular marker as prognosis and treatment for B-NHL. PMID:25798877

Song, Aiqin; Ye, Junli; Zhang, Kunpeng; Yu, Hongsheng; Gao, Yanhua; Wang, Hongfang; Sun, Lirong; Xing, Xiaoming; Yang, Kun; Zhao, Min

2015-05-01

13

Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes.  

PubMed

Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys(4) of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotide-binding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N(1)-acetylpolyamine oxidase). We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer. PMID:22132744

Wu, Yu; Steinbergs, Nora; Murray-Stewart, Tracy; Marton, Laurence J; Casero, Robert A

2012-03-15

14

Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes  

PubMed Central

Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys4 of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotide-binding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N1-acetylpolyamine oxidase). We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer. PMID:22132744

Wu, Yu; Steinbergs, Nora; Murray-Stewart, Tracy; Marton, Laurence J.; Casero, Robert A.

2011-01-01

15

Aberrant promoter methylation and expression of the imprinted PEG3 gene in glioma  

PubMed Central

Glioma includes astrocytoma, oligodendroglioma, ependymoma and glioblastoma. We previously reported the epigenetic silencing of paternally expressed gene 3 (PEG3) in glioma cell lines. In this study, we investigated methylation of an exonic CpG island in the promoter region and the expression of PEG3 gene in 20 glioma and 5 non-tumor tissue samples. We found wide variations in the methylation level. Hypomethylaiton and hypermethylation was found in 3 and 4 glioma tissue samples, respectively. Monoallelic expression, which is an evidence of an imprinted gene, was maintained in eight out of nine informative cases which have T/C polymorphisms in PEG3. The lower gene expression, which suggested epigenetic silencing of PEG3, was confirmed statistically in glioblastoma using quantitative reverse-transcription polymerase chain reaction. Interestingly, we found higher expression of PEG3 in two out of three oligodendrogliomas. A negative correlation between the methylation level and gene expression was shown by regression analysis. These results suggest that the abnormal regulation of PEG3 is associated with several glioma subtypes and that it plays an important role in tumorigenesis. PMID:19367087

Otsuka, Susumu; Maegawa, Shinji; Takamura, Ayumi; Kamitani, Hideki; Watanabe, Takashi; Oshimura, Mitsuo; Nanba, Eiji

2009-01-01

16

Fetal Onset of Aberrant Gene Expression Relevant to Pulmonary Carcinogenesis in Lung Adenocarcinoma Development Induced by In Utero Arsenic Exposure  

PubMed Central

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-? (ER-?) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-?-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. in utero arsenic exposure also induced overexpression of ?-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-? expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-? expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-? activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood. PMID:17077188

Shen, Jun; Liu, Jie; Xie, Yaxiong; Diwan, Bhalchandra A.; Waalkes, Michael P.

2009-01-01

17

Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.  

PubMed Central

Some human small cell lung carcinomas (SCLC) secrete proopiomelanocortin (POMC) derived peptides, but in contrast to the pituitary, glucocorticoids fail to inhibit this hormone production. We have previously described an in vitro model using human SCLC cell lines that express POMC and are resistant to glucocorticoids. We have now identified the glucocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay (Kd = 5.7 nM; Bmax = 11 fmol/million cells), while another cell line, DMS 79, lacked significant glucocorticoid binding. To analyze GR function both positive (GMCO) and negative (TRE)3-tkCAT), glucocorticoid-regulated reporter gene constructs were transfected into COR L24 cells. In the SCLC cell line, neither hydrocortisone nor dexamethasone (500-2,000 nM) significantly induced chloramphenicol acetyltransferase expression from GMCO; in addition, they did not suppress chloramphenicol acetyltransferase expression from (TRE)3-tkCAT. Similar results were obtained with two other POMC-expressing SCLC cell lines. Expression of wild type GR in COR L24 cells restored glucocorticoid signaling, with marked induction of GMCO reporter gene expression by dexamethasone (9,100 +/- 910%; n = 3), and an estimated EC50 of 10 nM. This failure of the GR explains the resistance of the POMC gene to glucocorticoid inhibition and may have implications for cell growth in SCLC. Images PMID:8163665

Ray, D W; Littlewood, A C; Clark, A J; Davis, J R; White, A

1994-01-01

18

Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations  

Microsoft Academic Search

Hematologic malignancies are characterized by fusion genes of biological\\/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23\\/MLL rearrangements, t(1;19)[TCF3\\/PBX1], t(12;21)[ETV6\\/RUNX1], t(8;21)[RUNX1\\/CBFA2T1], t(8;14)[IGH@\\/MYC], t(8;14)[TRA@\\/MYC], t(9;22)[BCR\\/ABL1], t(10;11)[PICALM\\/MLLT10], t(15;17)[PML\\/RARA], or inv(16)[CBFB\\/MYH11]. Unsupervised classification

A Andersson; P Edén; D Lindgren; J Nilsson; C Lassen; J Heldrup; M Fontes; Ĺ Borg; F Mitelman; B Johansson; M Höglund; T Fioretos

2005-01-01

19

Hyperacetylation in prostate cancer induces cell cycle aberrations, chromatin reorganization and altered gene expression profiles  

PubMed Central

Abstract Histone acetylation is a fundamental mechanism in the regulation of local chromatin conformation and gene expression. Research has focused on the impact of altered epigenetic environments on the expression of specific genes and their pathways. However, changes in histone acetylation also have a global impact on the cell. In this study we used digital texture analysis to assess global chromatin patterns following treatment with trichostatin A (TSA) and have observed significant alterations in the condensation and distribution of higher-order chromatin, which were associated with altered gene expression profiles in both immortalised normal PNT1A prostate cell line and androgen-dependent prostate cancer cell line LNCaP. Furthermore, the extent of TSA-induced disruption was both cell cycle and cell line dependent. This was illustrated by the identification of sub-populations of prostate cancer cells expressing high levels of H3K9 acetylation in the G2/M phase of the cell cycle that were absent in normal cell populations. In addition, the analysis of enriched populations of G1 cells showed a global decondensation of chromatin exclusively in normal cells. PMID:19583812

Watson, Jenny A; McKenna, Declan J; Maxwell, Perry; Diamond, James; Arthur, Ken; McKelvey-Martin, Valerie J; Hamilton, Peter W

2010-01-01

20

Aberrant transcripts of the FHIT gene are expressed in normal and leukaemic haemopoietic cells.  

PubMed Central

Deletions and apparent transcriptional abnormalities of the FHIT gene at 3p14.2 have recently been reported in a wide variety of solid tumours. To determine whether lesions of this gene also occur in leukaemia, we have analysed a total of 97 patients (chronic myeloid leukaemia, CML, in chronic phase or blast crisis, n = 71; de novo acute leukaemia, n = 26) and 16 normal individuals. Intact FHIT transcripts from all cases were amplified using RT-PCR. In addition, smaller size bands that were less intense than the full-length products were amplified from several samples from patients with leukaemia and also from normal leucocytes. Sequencing of the small products revealed that they were derived from FHIT transcripts lacking whole exons. Using single-strand conformation polymorphism analysis, no mutations in the coding sequence were detected in any patient. Furthermore, loss of heterozygosity was not seen in any of 36 informative patients at D3S1300 or D3S1481, markers located within the FHIT locus. We conclude that the FHIT gene and other uncharacterized tumour-suppressor genes at 3p14.2 are unlikely to be involved in the pathogenesis of acute leukaemia or progression of CML from chronic phase to blast crisis. Moreover, low-abundance FHIT transcripts that lack whole exons are not specific to malignant cells and should not be taken as evidence of an abnormality in the absence of demonstrable genomic DNA lesions. Images Figure 2 PMID:9744498

Carapeti, M.; Aguiar, R. C.; Sill, H.; Goldman, J. M.; Cross, N. C.

1998-01-01

21

Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer  

PubMed Central

Background A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response. Methods A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software). Results Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue. Conclusions The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients. PMID:24597571

2014-01-01

22

Myelomatous plasma cells display an aberrant gene expression pattern similar to that observed in normal memory B cells  

PubMed Central

Memory B cells (MBCs) remain in a quiescent state for years, expressing pro-survival and anti-apoptotic factors while repressing cell proliferation and activation genes. During their differentiation into plasma cells (PCs), their expression pattern is reversed, with a higher expression of genes related to cell proliferation and activation, and a lower expression of pro-survival genes. To determine whether myelomatous PCs (mPCs) share characteristics with normal PCs and MBCs and to identify genes involved in the pathophysiology of multiple myeloma (MM), we compared gene expression patterns in these three cell sub-types. We observed that mPCs had features intermediate between those of MBCs and normal PCs, and identified 3455 genes differentially expressed in mPCs relative to normal PCs but with a similar expression pattern to that in MBCs. Most of these genes are involved in cell death and survival, cell growth and proliferation and protein synthesis. According to our findings, mPCs have a gene expression pattern closer to a MBC than a PC with a high expression of genes involved in cell survival. These genes should be physiologically inactivated in the transit from MBC to PC, but remain overexpressed in mPCs and thus may play a role in the pathophysiology of the disease. PMID:25628947

Báez, Alicia; Piruat, José I; Caballero-Velázquez, Teresa; Sánchez-Abarca, Luís I; Álvarez-Laderas, Isabel; Barbado, M Victoria; García-Guerrero, Estefanía; Millán-Uclés, África; Martín-Sánchez, Jesús; Medrano, Mayte; Pérez-Simón, José Antonio

2015-01-01

23

High-resolution detection of recurrent aberrations in lung adenocarcinomas by array comparative genomic hybridization and expression analysis of selective genes by quantitative PCR.  

PubMed

Genomic abnormalities are the hallmark of cancers and may harbor potential candidate genes important for cancer development and progression. We performed array comparative genomic hybridization (array CGH) on 36 cases of primary lung adenocarcinoma (AD) using an array containing 2621 BAC or PAC clones spanning the genome at an average interval of 1 Mb. Array CGH identified the commonest aberrations consisting of DNA gains within 1p, 1q, 5p, 5q, 7p, 7q, 8q, 11q, 12p, 13q, 16p, 17q, 20q, and losses with 6q, 9p, 10q and 18q. High-level copy gains involved mainly 7p21-p15 and 20q13.3. Dual color fluorescence in situ hybridization (FISH) was performed on a selective locus for validation of array CGH results. Genomic aberrations were compared with different clinicopathological features and a trend of higher number of aberrations in tumors with aggressive phenotypes and current tobacco exposure was identified. According to array CGH data, 23 candidate genes were selected for quantitative PCR (qPCR) analysis. The concordance observed between the genomic and expression changes in most of the genes suggested that they could be candidate cancer-related genes that contributed to the development of lung AD. PMID:24728343

Zhu, Hong; Wong, Maria Pik; Tin, Vicky

2014-06-01

24

Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism  

SciTech Connect

Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17{beta}-hydroxysteroid dehydrogenase-7 (HSD17{beta}7; involved in estradiol production) and decreased expression of HSD17{beta}5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.

Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)]. E-mail: Liu6@niehs.nih.gov; Xie Yaxiong [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Cooper, Ryan [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Ducharme, Danica M.K. [National Center For Toxicogenomics, NIEHS, Research Triangle Park, NC (United States); Tennant, Raymond [National Center For Toxicogenomics, NIEHS, Research Triangle Park, NC (United States); Diwan, Bhalchandra A. [Basic Research Program, SAIC-Frederick, Inc., NCI Frederick, MD (United States); Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)

2007-05-01

25

Aberrant expression of homeobox gene HOXA7 is associated with müllerian-like differentiation of epithelial ovarian tumors and the generation of a specific autologous antibody response  

PubMed Central

Autologous serum antibodies to molecules that are aberrantly expressed in tumors represent potential biomarkers for early diagnosis of cancer. In this study, we identified the homeobox gene HOXA7 as encoding an antigen in epithelial tumors of the ovary. These tumors are thought to arise from the simple epithelium lining the ovarian surface, but they often resemble the specialized epithelia derived from the müllerian ducts. Expression of HOXA7 was detected in ovarian tumors exhibiting müllerian-like features and correlated with the generation of anti-HOXA7 antibodies by patients. In contrast, it was observed that healthy women lack anti-HOXA7 antibodies (P < 0.0001) and that HOXA7 expression is absent from normal ovarian surface epithelium. Interestingly, HOXA7 expression was detected in the müllerian-like epithelium lining inclusion cysts in normal ovaries and in the müllerian duct-derived epithelium of normal fallopian tubes. Furthermore, ectopic expression of HOXA7 enhanced the epithelial phenotype of immortalized ovarian surface epithelial cells, as indicated by the appearance of cobblestone morphology, induction of E-cadherin expression, and down-regulation of vimentin. These findings associate aberrant HOXA7 expression with the müllerian-like differentiation of epithelial ovarian tumors and suggest diagnostic utility of serum antibodies to HOXA7. PMID:11742062

Naora, Honami; Montz, Fredrick J.; Chai, Chee-Yin; Roden, Richard B. S.

2001-01-01

26

Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations  

PubMed Central

Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia. PMID:24441149

Abbas, Saman; Sanders, Mathijs A.; Zeilemaker, Annelieke; Geertsma-Kleinekoort, Wendy M.C.; Koenders, Jasper E.; Kavelaars, Francois G.; Abbas, Zabiollah G.; Mahamoud, Souad; Chu, Isabel W.T.; Hoogenboezem, Remco; Peeters, Justine K.; van Drunen, Ellen; van Galen, Janneke; Beverloo, H. Berna; Löwenberg, Bob; Valk, Peter J.M.

2014-01-01

27

Rex1 (Zfp42) Null Mice Show Impaired Testicular Function, Abnormal Testis Morphology, and Aberrant Gene Expression  

PubMed Central

Rex1(Zfp42), GeneID 132625, is a gene whose expression is closely associated with pluripotency/multipotency in both mouse and human embryonic stem cells. To study the function of the murine Rex1 gene in vivo, we have used cre/lox technology to create Rex1(floxed) mice and mice deficient in Rex1 gene function. Rex1-/- males are characterized by an age-associated decrease in sperm counts, abnormal sperm morphology, and mild testicular atrophy. We characterized global patterns of gene expression in primary germ cells by microarray and identified the growth hormone responsive gene, GRTP1, as a transcript present at a 4.5 fold higher level in wild type (WT) compared to Rex1-/- mice. We analyzed immature germ cell (Dazl), proliferating (PCNA), and Sertoli cell populations, and quantitated levels of apoptosis in Rex1-/- as compared to WT testes. We evaluated the expression of proteins previously reported to correlate with Rex1 expression, such as STAT3, phospho-STAT3, p38, and phospho-p38 in the testis. We report a distinct cellular localization of total STAT3 protein in Rex1-/- affected testes. Our data suggest that loss of Rex1 leads to impaired testicular function. PMID:21641340

Rezende, Naira; Lee, Mi-Young; Monette, Sébastien; Mark, Willie; Lu, Ailan; Gudas, Lorraine J.

2011-01-01

28

Gene Expression Meta-Analysis Identifies Cytokine Pathways and 5q Aberrations Involved in Metastasis of ERBB2 Amplified and Basal Breast Cancer  

PubMed Central

Background Breast tumors have been described by molecular subtypes characterized by pervasively different gene expression profiles. The subtypes are associated with different clinical parameters and origin of precursor cells. However, the biological pathways and chromosomal aberrations that differ between the subgroups are less well characterized. The molecular subtypes are associated with different risk of metastatic recurrence of the disease. Nevertheless, the performance of these overall patterns to predict outcome is far from optimal, suggesting that biological mechanisms that extend beyond the subgroups impact metastasis. Results We have scrutinized publicly available gene expression datasets and identified molecular subtypes in 1,394 breast tumors with outcome data. By analysis of chromosomal regions and pathways using “Gene set enrichment analysis” followed by a meta-analysis, we identified comprehensive mechanistic differences between the subgroups. Furthermore, the same approach was used to investigate mechanisms related to metastasis within the subgroups. A striking finding is that the molecular subtypes account for the majority of biological mechanisms associated with metastasis. However, some mechanisms, aside from the subtypes, were identified in a training set of 1,239 tumors and confirmed by survival analysis in two independent validation datasets from the same type of platform and consisting of very comparable node-negative patients that did not receive adjuvant medical therapy. The results show that high expression of 5q14 genes and low levels of TNFR2 pathway genes were associated with poor survival in basal-like cancers. Furthermore, low expression of 5q33 genes and interleukin-12 pathway genes were associated with poor outcome exclusively in ERBB2-like tumors. Conclusion The identified regions, genes, and pathways may be potential drug targets in future individualized treatment strategies. PMID:24327800

Thomassen, Mads; Tan, Qihua; Burton, Mark; Kruse, Torben A.

2013-01-01

29

Transplacental arsenic plus postnatal 12-O-teradecanoyl phorbol-13-acetate exposures associated with hepatocarcinogenesis induce similar aberrant gene expression patterns in male and female mouse liver  

SciTech Connect

Our prior work shows that in utero arsenic exposure alone is a complete transplacental carcinogen, producing hepatocellular carcinoma in adult male offspring but not in females. In a follow-up study to potentially promote arsenic-initiated tumors, mice were exposed to arsenic (85 ppm) from gestation day 8 to 18 and then exposed to 12-O-teradecanoyl phorbol-13-acetate (TPA), a well-known tumor promoter after weaning. The dermal application of TPA (2 {mu}g/0.1 ml acetone, twice/week for 21 weeks) after transplacental arsenic did not further increase arsenic-induced liver tumor formation in adult males but significantly increased liver tumor formation in adult females. Thus, for comparison, liver tumors and normal liver samples taken from adult male and female mice at necropsy were analyzed for aberrant gene/protein expression by microarray, real-time RT-PCR and Western blot analysis. Arsenic/TPA treatment resulted in increased expression of {alpha}-fetoprotein, k-ras, c-myc, estrogen receptor-{alpha}, cyclin D1, cdk2na, plasminogen activator inhibitor-1, cytokeratin-8, cytokeratin-18, glutathione S-transferases and insulin-like growth factor binding proteins in liver and liver tumors from both male and female mice. Arsenic/TPA also decreased the expression of BRCA1, betaine-homocysteine methyltransferase, CYP7B1, CYP2F2 and insulin-like growth factor-1 in normal and cancerous livers. Alterations in these gene products were associated with arsenic/TPA-induced liver tumors, regardless of sex. Thus, transplacental arsenic plus postnatal TPA exposure induced similar aberrant gene expression patterns in male and female mouse liver, which are persistent and potentially important to the mechanism of arsenic initiation of hepatocarcinogenesis.

Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)]. E-mail: Liu6@niehs.nih.gov; Xie Yaxiong [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Merrick, B. Alex [National Center for Toxicogenomics, NIEHS, Research Triangle Park, NC 27709 (United States); Shen Jun [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Ducharme, Danica M.K. [National Center for Toxicogenomics, NIEHS, Research Triangle Park, NC 27709 (United States); Collins, Jennifer [National Center for Toxicogenomics, NIEHS, Research Triangle Park, NC 27709 (United States); Diwan, Bhalchandra A. [Basic Research Program, SAIC, NCI-Frederick, Frederick, MD 21702 (United States); Logsdon, Daniel [Basic Research Program, SAIC, NCI-Frederick, Frederick, MD 21702 (United States); Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)

2006-06-15

30

Aberrant Expression of Clock Gene Period1 and Its Correlations with the Growth, Proliferation and Metastasis of Buccal Squamous Cell Carcinoma  

PubMed Central

Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P<0.05). PER1 expression was significantly down-regulated in patients of T3?T4 staging and those with lymph node metastasis compared to that of T1?T2 staging and those without lymph node metastasis (P<0.05), respectively. PER1 mRNA expression, MI and tumor weight had significant differences among the 4 time groups, which PI all confirmed to circadian rhythms. MI, PI, MMP-2 mRNA and tumor weight had negative correlation with PER1 mRNA expression. Peak value of PER1 mRNA expression and trough values of MI, PI and tumor weight all appeared in middle activity phase, whereas trough value of PER1 mRNA expression and peak values of MI, PI and tumor weight all occurred in middle rest phase. Our study suggested that aberrant expression of PER1 had significant correlation with the growth, proliferation and metastasis of BSCC and it might act as an anti-oncogene. PMID:23405233

Zhao, Ningbo; Yang, Kai; Yang, Genling; Chen, Dan; Tang, Hong; Zhao, Dan; Zhao, Chunrong

2013-01-01

31

Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells  

SciTech Connect

Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of {alpha}-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-{pi} and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 {mu}M, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation.

Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States)]. E-mail: Liu6@niehs.nih.gov; Benbrahim-Tallaa, Lamia [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Qian Xun [Laboratory of Signal Transduction, NIEHS (United States); Yu, Limei [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Zunyi Medical College, Zunyi (China); Xie Yaxiong [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Boos, Jennifer [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Qu Wei [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States)

2006-11-01

32

Tacrolimus Increases Nox4 Expression in Human Renal Fibroblasts and Induces Fibrosis-Related Genes by Aberrant TGF-Beta Receptor Signalling  

PubMed Central

Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-? is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the macrolide calcineurin inhibitor tacrolimus (FK-506) induced TGF-?-like effects, manifested by increased expression of NAD(P)H-oxidase 4 (Nox4), transgelin, tropomyosin 1, and procollagen ?1(V) mRNA after three days. The macrolide mTOR inhibitor rapamycin had similar effects, while cyclosporine A did not induce fibrose-related genes. Concentration dependence curves were sigmoid, where mRNA expression was induced already at low nanomolar levels of tacrolimus, and reached saturation at 100–300 nM. The effects were independent of extracellular TGF-? as confirmed by the use of neutralizing antibodies, and thus most likely caused by aberrant TGF-? receptor signaling, where binding of tacrolimus to the regulatory FKBP12 protein results in a “leaky” TGF-? receptor. The myofibroblast marker ?-smooth muscle actin was neither induced by tacrolimus nor by TGF-?1, indicating an incomplete activation of TK-173 fibroblasts under culture conditions. Tacrolimus- and TGF-?1-induced Nox4 protein upregulation was confirmed by Western blotting, and was accompanied by a rise in intracellular H2O2 concentration. Si-RNA mediated knock-down of Nox4 expression prevented up-regulation of procollagen ?1(V) mRNA in tacrolimus-treated cells, but induced procollagen ?1(V) expression in control cells. Nox4 knock-down had no significant effect on the other genes tested. TGF-? is a key molecule in fibrosis, and the constant activation of aberrant receptor signaling by tacrolimus might contribute to the long-term development of interstitial kidney fibrosis in immunosuppressed patients. Nox4 levels possibly play a regulatory role in these processes. PMID:24816588

Kern, Georg; Mair, Sabine M.; Noppert, Susie-Jane; Jennings, Paul; Schramek, Herbert; Rudnicki, Michael; Mueller, Gerhard A.; Mayer, Gert; Koppelstaetter, Christian

2014-01-01

33

Krüppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen.  

PubMed

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation, leading to progression of established neoplasms. PMID:21543766

Simmons, Christian D; Pabona, John Mark P; Heard, Melissa E; Friedman, Theodore M; Spataro, Michael T; Godley, Amy L; Simmen, Frank A; Burnett, Alexander F; Simmen, Rosalia C M

2011-08-01

34

Krüppel-Like Factor 9 Loss-of-Expression in Human Endometrial Carcinoma Links Altered Expression of Growth-Regulatory Genes with Aberrant Proliferative Response to Estrogen1  

PubMed Central

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation, leading to progression of established neoplasms. PMID:21543766

Simmons, Christian D.; Pabona, John Mark P.; Heard, Melissa E.; Friedman, Theodore M.; Spataro, Michael T.; Godley, Amy L.; Simmen, Frank A.; Burnett, Alexander F.; Simmen, Rosalia C.M.

2011-01-01

35

Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen  

Technology Transfer Automated Retrieval System (TEKTRAN)

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like Factor 9 (KLF9), a member of the evolutionarily conserved Sp-family of transcription factors, is expressed in uterine stroma and glandular epithelium where it affects cellular proliferation, differenti...

36

Aberrant phenotype and transcriptome expression during fiber cell wall thickening caused by the mutation of the Im gene in immature fiber (im) mutant in Gossypium hirsutum L  

PubMed Central

Background The immature fiber (im) mutant of Gossypium hirsutum L. is a special cotton fiber mutant with non-fluffy fibers. It has low dry weight and fineness of fibers due to developmental defects in fiber secondary cell wall (SCW). Results We compared the cellulose content in fibers, thickness of fiber cell wall and fiber transcriptional profiling during SCW development in im mutant and its near-isogenic wild-type line (NIL) TM-1. The im mutant had lower cellulose content and thinner cell walls than TM-1 at same fiber developmental stage. During 25?~?35 day post-anthesis (DPA), sucrose content, an important carbon source for cellulose synthesis, was also significantly lower in im mutant than in TM-1. Comparative analysis of fiber transcriptional profiling from 13?~?25 DPA indicated that the largest transcriptional variations between the two lines occurred at the onset of SCW development. TM-1 began SCW biosynthesis approximately at 16 DPA, whereas the same fiber developmental program in im mutant was delayed until 19 DPA, suggesting an asynchronous fiber developmental program between TM-1 and im mutant. Functional classification and enrichment analysis of differentially expressed genes (DEGs) between the two NILs indicated that genes associated with biological processes related to cellulose synthesis, secondary cell wall biogenesis, cell wall thickening and sucrose metabolism, respectively, were significantly up-regulated in TM-1. Twelve genes related to carbohydrate metabolism were validated by quantitative reverse transcription PCR (qRT-PCR) and confirmed a temporal difference at the earlier transition and SCW biosynthesis stages of fiber development between TM-1 and im mutant. Conclusions We propose that Im is an important regulatory gene influencing temporal differences in expression of genes related to fiber SCW biosynthesis. This study lays a foundation for cloning the Im gene, elucidating molecular mechanism of fiber SCW development and further genetic manipulation for the improvement of fiber fineness and maturity. PMID:24483163

2014-01-01

37

Dd-STATb, a Dictyostelium STAT protein with a highly aberrant SH2 domain, functions as a regulator of gene expression during growth and early development.  

PubMed

Dictyostelium, the only known non-metazoan organism to employ SH2 domain:phosphotyrosine signaling, possesses STATs (signal transducers and activators of transcription) and protein kinases with orthodox SH2 domains. Here, however, we describe a novel Dictyostelium STAT containing a remarkably divergent SH2 domain. Dd-STATb displays a 15 amino acid insertion in its SH2 domain and the conserved and essential arginine residue, which interacts with phosphotyrosine in all other known SH2 domains, is substituted by leucine. Despite these abnormalities, Dd-STATb is biologically functional. It has a subtle role in growth, so that Dd-STATb-null cells are gradually lost from the population when they are co-cultured with parental cells, and microarray analysis identified several genes that are either underexpressed or overexpressed in the Dd-STATb null strain. The best characterised of these, discoidin 1, is a marker of the growth-development transition and it is overexpressed during growth and early development of Dd-STATb null cells. Dimerisation of STAT proteins occurs by mutual SH2 domain:phosphotyrosine interactions and dimerisation triggers STAT nuclear accumulation. Despite its aberrant SH2 domain, the Dd-STATb protein sediments at the size expected for a homodimer and it is constitutively enriched in the nucleus. Moreover, these properties are retained when the predicted site of tyrosine phosphorylation is substituted by phenylalanine. These observations suggest a non-canonical mode of activation of Dd-STATb that does not rely on orthodox SH2 domain:phosphotyrosine interactions. PMID:14701681

Zhukovskaya, Natasha V; Fukuzawa, Masashi; Tsujioka, Masatsune; Jermyn, Keith A; Kawata, Takefumi; Abe, Tomoaki; Zvelebil, Marketa; Williams, Jeffrey G

2004-01-01

38

Gene Expression Mural: Visualizing Gene Expression Databases  

E-print Network

Gene Expression Mural: Visualizing Gene Expression Databases Mathew Clement, Margaret Ellis, Josh@cs.vt.edu Abstract The Gene Expression Mural is a tool designed for managing the vast amount of information produced quantifying the expression level of gene sequences in a number of conditions [1]. Software tools integrating

39

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes  

PubMed Central

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID:23103869

Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

2012-01-01

40

Methylation and expression analysis of 15 genes and three normally-methylated genes in 13 Ovarian cancer cell lines  

Microsoft Academic Search

Aberrant methylation of CpG islands (CGIs) in promoter regions of tumor-suppressor genes causes their silencing, and aberrant demethylation of normally methylated CGIs in promoter regions causes aberrant expression of cancer-testis antigens. Here, we comprehensively analyzed aberrant methylation of 15 genes and demethylation of three normally methylated genes in 13 ovarian cancer cell lines. RASSF1A was most frequently methylated (complete methylation

Masayoshi Imura; Satoshi Yamashita; Li-yi Cai; Jun-ichi Furuta; Mika Wakabayashi; Toshiharu Yasugi; Toshikazu Ushijima

2006-01-01

41

Clustering gene expression data  

E-print Network

CG 1 Clustering gene expression data #12;CG 2 How Gene Expression Data Looks Expression levels, "Raw Data" conditions genes Entries of the Raw Data matrix: · Ratio values · Absolute values · ... · Row = gene's expression pattern · Column = experiment/condition's profile #12;CG 3 Data Preprocessing

Shamir, Ron

42

Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice.  

PubMed Central

Interferons (IFNs) are well known both as antiviral proteins and as potent regulators of cell growth and differentiation. In fact, IFNs inhibit growth of various normal and transformed cell types. Previously, a nuclear factor, IRF-1 (interferon regulatory factor 1), which binds to type I IFN and some IFN-inducible gene promoters, was identified and cloned. Since the IRF-1 gene is both virus and IFN inducible, an intriguing issue is raised as to whether the IRF-1 gene is functioning in IFN-mediated regulation of cell growth and differentiation. In this study, we generated transgenic mice carrying the human IRF-1 gene linked to the human immunoglobulin heavy-chain enhancer. In the transgenic mice, all the lymphoid tissues examined showed a dramatic reduction in the number of B lymphocytes (B cells). Preparation and analysis of bone marrow cells from the chimeric mice indicated that the bone marrow is the effective site for specific depletion of the B-cell population. In fact, transgenic bone marrow cells cocultured with a bone marrow-derived stromal cell line revealed an altered B-cell maturation pattern. Images PMID:1988951

Yamada, G; Ogawa, M; Akagi, K; Miyamoto, H; Nakano, N; Itoh, S; Miyazaki, J; Nishikawa, S; Yamamura, K; Taniguchi, T

1991-01-01

43

Clustering gene expression patterns  

Microsoft Academic Search

Recent advances in biotechnology allow researchers to measure expression levels for thousands of genes simultaneously, across different conditions and over time. Analysis of data produced by such experiments offers potential insight into gene function and regulatory mechanisms. A key step in the analysis of gene expression data is the detection of groups of genes that manifest similar expression patterns. The

Amir Ben-Dor; Zohar Yakhinit; Zohar Yakhini

1999-01-01

44

WISP Genes are Members of the Connective Tissue Growth Factor Family that are Up-Regulated in Wnt1-Transformed Cells and Aberrantly Expressed in Human Colon Tumors  

Microsoft Academic Search

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third

Diane Pennica; Todd A. Swanson; James W. Welsh; Margaret A. Roy; David A. Lawrence; James Lee; Jennifer Brush; Lisa A. Taneyhill; Bethanne Deuel; Michael Lew; Colin Watanabe; Robert L. Cohen; Mona F. Melhem; Gene G. Finley; Phil Quirke; Audrey D. Goddard; Kenneth J. Hillan; Austin L. Gurney; David Botstein; Arnold J. Levine

1998-01-01

45

Metabolic gene variants associated with chromosomal aberrations in healthy humans.  

PubMed

Nonspecific chromosomal aberrations (CAs) are found in about 1% of lymphocytes drawn from healthy individuals. They include chromosome-type aberrations (CSAs), which are increased in exposure to ionizing radiation, and chromatid-type aberrations (CTAs) which in experimental systems are formed by DNA binding carcinogens and mutagens. The frequency of CAs is associated with the risk of cancer, but the causes of CAs in general population are unknown. Here, we want to test whether variants in metabolic genes associate with CAs in healthy volunteers. Cases were considered those whose total CA (CAtot) frequency was >2% and for CSA and CTA the limit was >1%. Controls had lower frequencies of CAs. Functional polymorphisms in seven genes were selected for analysis: cytochrome P450 1B1 (CYP1B1), epoxide hydrolase 1 (EPHX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), each coding for phase 1 enzymes, and glutathione S-transferase P1 (GSTP1), glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), coding for enzymes which conjugate reactive metabolites, that is, phase 2 enzymes. The number of volunteers genotyped for each gene varied from 550 to 1,500. Only EPHX1 was individually associated with CAtot; high activity genotypes decreased CAtot. A total of six significant (P < 0.01) pair-wise interactions were observed, most including a GST variant as one of the pair. In all genotype combinations with significant odds ratios for CAs a GST variant was involved. The present data provide evidence that variants in genes coding for metabolic enzymes, which individually have small effects, interact and are associated with CA frequencies in peripheral lymphocytes of healthy volunteers. © 2015 Wiley Periodicals, Inc. PMID:25622915

Hemminki, Kari; Frank, Christoph; Försti, Asta; Musak, Ludovit; Kazimirova, Alena; Barancokova, Magdalena; Horska, Alexandra; Vymetalkova, Veronika; Smerhovsky, Zdenek; Naccarati, Alessio; Soucek, Pavel; Vodickova, Ludmila; Buchancova, Janka; Smolkova, Bozena; Dusinska, Maria; Vodicka, Pavel

2015-04-01

46

Gastric-type endocervical glandular neoplasms associated with aberrant p16 expression and K-RAS gene mutation in Peutz-Jeghers syndrome.  

PubMed

In this report, unique endocervical glandular lesions exhibiting gastric differentiation were examined in a patient with Peutz-Jeghers syndrome. The result of the human papillomavirus (HPV) in situ hybridization (ISH) for the hysterectomy specimens was negative, but they demonstrated a papillary mucinous adenocarcinoma at the proximal endocervix continuous to atypical lobular endocervical glandular hyperplasia. Both contained MUC6-positive neutral mucin in cytoplasm, and showed different immunoreactivity to p16, Ki-67, and p53. Moreover, they harbored the identical K-RAS gene mutation suggesting that there was a common origin. Somatic K-RAS mutation and defective function of p16 may have been involved in the tumorigenesis of these unusual mucinous neoplasms. PMID:24965111

Ito, Shigemi; Tase, Toru; Satoh, Kennichi; Ueki, Miyuki; Sato, Ikuro; Sasano, Hironobu

2014-06-01

47

Gene expression heterogeneous  

E-print Network

Magazine R359 Gene expression becomes heterogeneous with age Mehmet Somel1*, Philipp Khaitovich1 for an age-dependent increase in variation in gene expression has yet been found [6­9]. Using eight microarray data sets from different studies in humans and rats, we find that gene expression becomes more

Khaitovich, Philipp

48

Aberrant methylation of the PTCH1 gene promoter region in aberrant crypt foci.  

PubMed

Patched homolog 1 (PTCH1) is a known tumor suppressor that regulates the Hedgehog (Hh) pathway and has been implicated in tumorigenesis. The role of PTCH1 in colon carcinogenesis, however, is controversial. The aim of the present study was to investigate epigenetic modifications of PTCH1 in aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancer (CRC). Using laser-capture microdissection (LCM), a pure population of ACF epithelial cells was isolated and studied. The inherent protein expression levels of SHH, PTCH1, SMO and GLI1 were assessed by immunohistochemistry for 405 ACF, including 54 dysplastic ACF (d-ACF) and 351 non-dysplastic ACF (n-ACF). The mRNA levels and methylation status of PTCH1 were also determined in 54 d-ACF and 96 n-ACF. Our data showed that the expression of SHH, SMO and GLI1 was significantly up-regulated in d-ACF, compared to n-ACF. Also, the mRNA and protein levels of PTCH1 were lower in d-ACF than n-ACF. Using MSP or MS-HRM, PTCH1 methylation was present in 64.8% (35/54) or 63.3% (34/54), respectively, of d-ACF and 19.8% (19/96) or 22.9% (11/48), respectively, of n-ACF. PTCH1 methylation was more frequent in d-ACF than n-ACF (p < 0.001) and was associated with PTCH1 mRNA levels (r = 0.358, p < 0.01). There was a statistically significant correlation between PTCH1 methylation status and the prevalence of colorectal neoplasms. In conclusion, this study suggests that aberrant methylation of the PTCH1 promoter may be an early, initiating event of colon carcinogenesis. PMID:22945423

Peng, Liang; Hu, Jingjing; Li, Shujun; Wang, Zhongqiu; Xia, Bingqing; Jiang, Bo; Li, Bingsheng; Zhang, Yu; Wang, Jing; Wang, Xinying

2013-01-15

49

Aberrant expression of TSG101 in Taiwan Chinese breast cancer  

Microsoft Academic Search

Functional inactivation of the tsg101 gene in mouse fibroblasts results in cell transformation and the ability to form metastatic tumors in nude mice. The human tsg101 gene was mapped to chromosome 11q15.1-2 and found to mutate in some cancer patients. To test the expression pattern of the tsg101 gene in Chinese breast cancer patients, we analyzed the mRNA by RT-PCR

Yung-Feng Lo; Tse-Ching Chen; Shin-Cheh Chen; Chuck-K. C. Chao

2000-01-01

50

ABERRANT CYTOPLASMIC EXPRESSION OF P63 AND PROSTATE CANCER MORTALITY  

PubMed Central

Protein expression of p63 is used to differentiate prostate cancer from benign mimickers. Recent studies suggest that it may also distinguish aggressive prostate cancer with down-regulated expression occurring in men with more advanced disease. We conducted a prospective study among 298 men aged 51–84 years who were diagnosed with prostate cancer in the Physicians’ Health Study in 1983–2004 and whose tissue was available for immunohistochemical (IHC) staining. We used Cox proportional hazards regression to evaluate the association of p63 protein expression with fatal prostate cancer. We correlated p63 expression with tumor cell proliferation (ki67) and apoptosis (TUNEL staining). The predominant location of tumor p63 staining occurred in the cytoplasm, an uncommon departure from the strong nuclear staining usually observed in non-neoplastic basal cells. Increasing expression of cytoplasmic p63 (tertiles) was associated with prostate cancer mortality (n=19 deaths); the hazard ratios and 95% confidence intervals were: 1.0 [referent], 4.0 (0.9, 18.9) and 5.9 (1.3, 27.5), p for trend = .03). The positive trend remained significant (p=.047) after multivariable adjustment for age, year of diagnosis and Gleason score. Higher tertiles of cytoplasmic p63 were also associated with reduced levels of apoptosis (p for trend = 0.0408) and increased cellular proliferation (p for trend = 0.0026). We found aberrant expression of p63 in the cytoplasm to be associated with increased prostate cancer-specific mortality up to 20 years after diagnosis. The mislocalized expression was associated with reduced apoptosis and higher proliferative activity, and may suggest an oncogenic role in prostate cancer progression and survival. PMID:19155438

Dhillon, Preet K.; Barry, Marc; Stampfer, Meir J; Perner, Sven; Fiorentino, Michelangelo; Fornari, Alessandro; Ma, Jing; Fleet, Julia; Kurth, Tobias; Rubin, Mark A.; Mucci, Lorelei A.

2009-01-01

51

Identification of two aberrant transcripts derived from a hybridoma with amplification of functional immunoglobulin variable genes  

PubMed Central

Murine monoclonal antibodies (mAbs) are widely used but have limitations if administered in humans. The use of chimeric or humanized mAbs can reduce immunogenicity. The first step in producing such mAbs is to clone murine variable genes from a hybridoma, but it is possible to amplify both functional and aberrant variable genes, as they coexist in the hybridoma. During the development of a murine–human chimeric antibody, we have cloned from a hybridoma the functional heavy chain variable region (VH) and light chain variable region (VL) genes of a mAb that blocks the binding of anthrax lethal factor to protective antigen. In this study, we report the detection of two aberrant transcripts from a hybridoma produced using myeloma cell line OUR-1, the development of a method to distinguish between the functional and abundant aberrant VL transcripts, and the origins of these aberrant genes. The aberrant VL gene is derived from OUR-1 cells, while the aberrant VH gene might derive from antibody repertoires in B cells or from gene rearrangement in the hybridoma cells. The aberrant VH and VL genes in this study may facilitate discrimination between the functional and aberrant variable genes from hybridoma cells. PMID:20657605

Ding, Guipeng; Chen, Ximin; Zhu, Jin; Cao, Brian

2010-01-01

52

Aberrant Expression of COT Is Related to Recurrence of Papillary Thyroid Cancer.  

PubMed

Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n?=?167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P?expression of COT mRNA in PTC showed positive correlation with A- (r?=?0.4083, P?expressions of A-, B,- and C-RAF were also correlated with each other (all P?aberrant expression of COT was related to old age at initial diagnosis (P?=?0.045) and higher recurrence rate (P?=?0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066?-?21.609; P?=?0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2?±?4.1 years; P?=?0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P?expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P?Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC. PMID:25674762

Lee, Jandee; Jeong, Seonhyang; Park, Jae Hyun; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Lee, Eun Jig; Chung, Woong Youn; Jo, Young Suk

2015-02-01

53

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids.  

PubMed

Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development. PMID:23704310

Zaitseva, Marina; Holdsworth-Carson, Sarah J; Waldrip, Luke; Nevzorova, Julia; Martelotto, Luciano; Vollenhoven, Beverley J; Rogers, Peter A W

2013-08-01

54

Gene expression analysis identifies global gene dosage sensitivity in cancer.  

PubMed

Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying this method to 16,172 patient-derived tumor samples, we replicated many loci with aberrant copy numbers and identified recurrently disrupted genes in genomically unstable cancers. PMID:25581432

Fehrmann, Rudolf S N; Karjalainen, Juha M; Krajewska, Ma?gorzata; Westra, Harm-Jan; Maloney, David; Simeonov, Anton; Pers, Tune H; Hirschhorn, Joel N; Jansen, Ritsert C; Schultes, Erik A; van Haagen, Herman H H B M; de Vries, Elisabeth G E; Te Meerman, Gerard J; Wijmenga, Cisca; van Vugt, Marcel A T M; Franke, Lude

2015-02-01

55

Aberrant expression of interferon regulatory factor 3 in human lung cancer  

SciTech Connect

We analyzed the subcellular distributions and gene structures of interferon regulatory factor 3 (IRF3) transcription factor in 50 cases of human primary lung cancer. The immunohistochemical analyses revealed substantially aberrant IRF3 expression specific to the cancer lesions (2 and 6 tumors with nuclear staining, and 4 and 5 tumors with negative staining, in adenocarcinoma and squamous cell carcinoma, respectively), while the morphologically normal region around the tumors exhibited only cytoplasmic staining. In addition, we determined the sequence of the entire IRF3 coding region, and found two novel variants with the amino acid changes (S{sup 175}(AGC) {yields} R{sup 175}(CGC) and A{sup 208}(GCC) {yields} D{sup 208}(GAC)). The R{sup 175} variant was also detected in a morphologically normal region around the nuclear staining squamous cell carcinoma, and exhibited almost the same functions as the wild type IRF3. On the other hand, the D{sup 208} variant, found in the negative staining squamous cell carcinoma cases, reduced the nuclear translocation in response to I{kappa}B kinase {epsilon} stimulation, as compared to the wild type IRF3, but the same variant was detected in the surrounding morphologically normal region. The aberrant expression of IRF3 and the novel D{sup 208} variant may provide clues to elucidate the etiology of primary lung cancer.

Tokunaga, Takayuki [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan) [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Naruke, Yuki; Shigematsu, Sayuri; Kohno, Tomoko; Yasui, Kiyoshi; Ma, Yuhua; Chua, Koon Jiew [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Katayama, Ikuo; Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Department of Radiology and Cancer Biology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Hishikawa, Yoshitaka; Koji, Takehiko [Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Yatabe, Yasushi [Department of Pathology and Clinical Oncology, Aichi Cancer Research Institute, Nagoya 464-8681 (Japan)] [Department of Pathology and Clinical Oncology, Aichi Cancer Research Institute, Nagoya 464-8681 (Japan); Nagayasu, Takeshi [Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Fujita, Takashi [Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan)] [Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan); Matsuyama, Toshifumi, E-mail: tosim@nagasaki-u.ac.jp [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan) [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); The Global Center of Excellence Program at Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); and others

2010-06-25

56

Aberrant expression of beta-HCG in anaplastic large cell lymphoma.  

PubMed

We report a case of anaplastic large cell lymphoma (ALCL) showing aberrant expression of beta subunit of human chorionic gonadotrophin (beta-HCG). The patient was a 14-year-old boy who presented with a right inguinal mass and a raised serum beta-HCG level. Biopsy of the mass revealed a malignant neoplasm composed of large, pleomorphic cells with prominent nucleoli. These malignant cells showed positive staining with CD30, ALK, epithelial membrane antigen, and beta-HCG. Chromosomal analysis showed t(2;5)(p23;q35) translocation, and polymerase chain reaction demonstrated T-cell receptor gene rearrangement. The patient did not respond well to chemotherapy, and he died 8 months after the diagnosis. To the best of our knowledge, this is the 1st case of ALCL showing aberrant expression of beta-HCG and associated with a raised serum level of beta-HCG. We report this case to bring awareness of this presumably rare occurrence to avoid the risk of misdiagnosis. PMID:17990918

Leong, May Ying; English, Martin; McMullan, Dominic; Ramani, Pramila

2008-01-01

57

Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism  

PubMed Central

Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminally differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA-induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinson's disease. PMID:25254549

Lerdrup, Mads; Gomes, Ana-Luisa; Kryh, Hanna; Spigolon, Giada; Caboche, Jocelyne; Fisone, Gilberto; Hansen, Klaus

2014-01-01

58

Focal Chromosomal Copy Number Aberrations Identify CMTM8 and GPR177 as New Candidate Driver Genes in Osteosarcoma  

PubMed Central

Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesis. PMID:25551557

Bras, Johannes; Schaap, Gerard R.; Baas, Frank; Ylstra, Bauke; Hulsebos, Theo J. M.

2014-01-01

59

Visualizing differentially expressed genes  

NASA Astrophysics Data System (ADS)

Identification of significantly differentially expressed genes (marker genes) among sample groups is a central issue in microarray analysis. This identification is important to understand the molecular pathway of diseases. Many statistical methods have been proposed to locate marker genes. These methods depend on a cutoff value for selection. A tightfisted cutoff may omit some of the important marker genes, whereas a generous threshold increases the number of false positives. Although robust models for identifying marker genes more accurately is an area of intense research, effective tools for the evaluation of results is often ignored in the literature. Despite the robustness of many of these methods, there is always some probability of false positives. In this paper, we propose a novel approach that exploits parallel coordinates to visualize the gene expression patterns so that one can compare the expression level changes of the marker genes between sample groups and determine whether the selected marker genes are valid. Such visualization is useful to measure the validity of the marker gene selection process as well as to fine tune the parameters of a particular method. A prediction method based on the selected marker genes is used to measure the reliability of our process.

Islam, Atiq U.; Iftekharuddin, Khan M.; Russomanno, David J.

2006-08-01

60

Aberrant methylation of ERBB pathway genes in sporadic colorectal cancer.  

PubMed

The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients. However, in contrast to genetic events, little is known about epigenetic alternations of ErbB-associated genes and their impact on gene expression. Genome-wide methylation in sporadic CRCs (n?=?12) paired with adjacent normal tissues have been previously analysed by Illumina Infinium HumanMethylation27 (HM27) at 27,578 CpG sites. For confirmation of our initial genome-wide analysis, we used a published HM27 dataset (GSE25062). Subsequently, CpG island methylation of selected ErbB pathway-associated genes was assessed on 233 CRC samples using methylation-sensitive polymerase chain reaction (MS-PCR) and analysed along with various genetic factors associated with CRC [epigenotype, BRAF and KRAS mutations, microsatellite instability (MSI)]. Methylation and expression integration was performed using published datasets including 25 pairs of CRC and normal colon tissues (GSE25062 and GSE25070), and confirmed with real-time PCR. Our previous microarray-based genome-wide DNA methylation analysis of 12 CRCs revealed that four ErbB-associated genes (PIK3CD, PKC?, ERBB4, ) were differentially methylated in CRCs. This was further confirmed by statistical re-analysis of an HM27 dataset (GSE25062). Frequent methylation at these loci in tumours was subsequently confirmed by MS-PCR (63 %, 43 %, 43 % and 92 %, respectively). Hypermethylation of PKC? associated with KRAS mutation (p?=?0.04), whereas hypermethylation of ERBB4 associated with high-methylation epigenotypes (HME), BRAF mutation and MSI (p?=?0.001, 0.002 and 0.0002, respectively). One of the four analysed genes (PKC?) was significantly downregulated in CRC tissue, as revealed by real-time PCR and re-analysis of the GSE25062 and GSE25070 datasets. After careful re-analysis of published methylation and expression data, we conclude that methylation of ERBB4, PAK7 and PIK3CD has no functional role in CRC carcinogenesis. In contrast, methylation seems to have a potential impact on the biology of colorectal tumours by negatively modulating the expression of PKC?. Importantly, the relationship between DNA methylation of PKC? and gene expression may warrant further attention in the context of colon cancer chemoprevention and anti-cancer therapy. PMID:25366420

Szmida, Elzbieta; Karpi?ski, Pawel; Leszczynski, Przemyslaw; Sedziak, Tomasz; Kielan, Wojciech; Ostasiewicz, Pawe?; Sasiadek, Maria M

2015-05-01

61

GENE EXPRESSION NETWORKS  

EPA Science Inventory

"Gene expression network" is the term used to describe the interplay, simple or complex, between two or more gene products in performing a specific cellular function. Although the delineation of such networks is complicated by the existence of multiple and subtle types of intera...

62

GENE EXPRESSION PROFILING  

Technology Transfer Automated Retrieval System (TEKTRAN)

DNA microarray technology is fast becoming a standard tool for gene expression analysis. The laboratory methods and protocols for array construction, processing, and hybridization are well established. Many of the initial plant genome sequencing projects are providing large sets of expressed seque...

63

Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations  

PubMed Central

We previously identified a rearrangement of mixed-lineage leukemia (MLL) gene (also known as ALL-1, HRX, and HTRX1), consisting of an in-frame partial tandem duplication (PTD) of exons 5 through 11 in the absence of a partner gene, occurring in approximately 4%–7% of patients with acute myeloid leukemia (AML) and normal cytogenetics, and associated with a poor prognosis. The mechanism by which the MLL PTD contributes to aberrant hematopoiesis and/or leukemia is unknown. To examine this, we generated a mouse knockin model in which exons 5 through 11 of the murine Mll gene were targeted to intron 4 of the endogenous Mll locus. MllPTD/WT mice exhibit an alteration in the boundaries of normal homeobox (Hox) gene expression during embryogenesis, resulting in axial skeletal defects and increased numbers of hematopoietic progenitor cells. MllPTD/WT mice overexpress Hoxa7, Hoxa9, and Hoxa10 in spleen, BM, and blood. An increase in histone H3/H4 acetylation and histone H3 lysine 4 (Lys4) methylation within the Hoxa7 and Hoxa9 promoters provides an epigenetic mechanism by which this overexpression occurs in vivo and an etiologic role for MLL PTD gain of function in the genesis of AML. PMID:16981007

Dorrance, Adrienne M.; Liu, Shujun; Yuan, Weifeng; Becknell, Brian; Arnoczky, Kristy J.; Guimond, Martin; Strout, Matthew P.; Feng, Lan; Nakamura, Tatsuya; Yu, Li; Rush, Laura J.; Weinstein, Michael; Leone, Gustavo; Wu, Lizhao; Ferketich, Amy; Whitman, Susan P.; Marcucci, Guido; Caligiuri, Michael A.

2006-01-01

64

Gene structure and expression  

SciTech Connect

This book describes the structure of genes in molecular terms and summarizes present knowledge about how their activity is regulated. It covers a range of topics, including a review of the structure and replication of DNA, transcription and translation, prokaryotic and eukaryotic gene organization and expression, retroviruses and oncogenes. The book also includes a chapter on the methodology of DNA manipulation including sections on site-directed mutagenesis, the polymerase chain reaction, reporter genes and restriction fragment length polymorphisms. The hemoglobin gene system and the genetics of the proteins of the immune system are presented in the latter half of the book to show the structure and expression of the most well-studied systems in higher eukaryotes. The final chapter reviews the differences between prokaryotic and the eukaryotic genomes.

Hawkins, J. (London Univ. (United Kingdom))

1990-01-01

65

TGF-{beta}-stimulated aberrant expression of class III {beta}-tubulin via the ERK signaling pathway in cultured retinal pigment epithelial cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer TGF-{beta} induces aberrant expression of {beta}III in RPE cells via the ERK pathway. Black-Right-Pointing-Pointer TGF-{beta} increases O-GlcNAc modification of {beta}III in RPE cells. Black-Right-Pointing-Pointer Mature RPE cells have the capacity to express a neuron-associated gene by TGF-{beta}. -- Abstract: The class III {beta}-tubulin isotype ({beta}{sub III}) is expressed exclusively by neurons within the normal human retina and is not present in normal retinal pigment epithelial (RPE) cells in situ or in the early phase of primary cultures. However, aberrant expression of class III {beta}-tubulin has been observed in passaged RPE cells and RPE cells with dedifferentiated morphology in pathologic epiretinal membranes from idiopathic macular pucker, proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Transforming growth factor-{beta} (TGF-{beta}) has been implicated in dedifferentiation of RPE cells and has a critical role in the development of proliferative vitreoretinal diseases. Here, we investigated the potential effects of TGF-{beta} on the aberrant expression of class III {beta}-tubulin and the intracellular signaling pathway mediating these changes. TGF-{beta}-induced aberrant expression and O-linked-{beta}-N-acetylglucosamine (O-GlcNac) modification of class III {beta}-tubulin in cultured RPE cells as determined using Western blotting, RT-PCR and immunocytochemistry. TGF-{beta} also stimulated phosphorylation of ERK. TGF-{beta}-induced aberrant expression of class III {beta}-tubulin was significantly reduced by pretreatment with U0126, an inhibitor of ERK phosphorylation. Our findings indicate that TGF-{beta} stimulated aberrant expression of class III {beta}-tubulin via activation of the ERK signaling pathway. These data demonstrate that mature RPE cells have the capacity to express a neuron-associated gene in response to TGF-{beta} stimulation and provide useful information towards understanding the pathogenesis of proliferative vitreoretinal diseases.

Chung, Eun Jee [Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do (Korea, Republic of)] [Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do (Korea, Republic of); Chun, Ji Na; Jung, Sun-Ah [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of)] [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of); Cho, Jin Won [Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749 (Korea, Republic of)] [Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Lee, Joon H., E-mail: joonhlee@konyang.ac.kr [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of)

2011-11-18

66

Aberrant Glycosphingolipid Expression and Membrane Organization in Tumor Cells: Consequences on Tumor–Host Interactions  

Microsoft Academic Search

\\u000a More than 20 years ago [1], the pioneering work of Dr. Sen-itiroh Hakomori formed the basis for the concept that aberrant\\u000a glycosylation is a general feature of human cancer. The term “aberrant glycosylation” describes the altered expression of\\u000a oligosaccharide epitopes associated with both glycolipid and glycoprotein antigens in human cancer. This event is the consequence\\u000a of at least two different

Alessandro Prinetti; Simona Prioni; Nicoletta Loberto; Massimo Aureli; Valentina Nocco; Giuditta Illuzzi; Laura Mauri; Manuela Valsecchi; Vanna Chigorno; Sandro Sonnino

67

Acquired Alterations of Hypothalamic Gene Expression of Insulin and Leptin Receptors and Glucose Transporters in Prenatally High-Glucose Exposed Three-Week Old Chickens Do Not Coincide with Aberrant Promoter DNA Methylation  

PubMed Central

Background Prenatal exposures may have a distinct impact for long-term health, one example being exposure to maternal ‘diabesity’ during pregnancy increasing offspring ‘diabesity’ risk. Malprogramming of the central nervous regulation of body weight, food intake and metabolism has been identified as a critical mechanism. While concrete disrupting factors still remain unclear, growing focus on acquired epigenomic alterations have been proposed. Due to the independent development from the mother, the chicken embryo provides a valuable model to distinctively establish causal factors and mechanisms. Aim The aim of this study was to determine the effects of prenatal hyperglycemia on postnatal hypothalamic gene expression and promoter DNA methylation in the chicken. Methods and Findings To temporarily induce high-glucose exposure in chicken embryos, 0.5 ml glucose solution (30 mmol/l) were administered daily via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. At three weeks of postnatal age, body weight, total body fat, blood glucose, mRNA expression (INSR, LEPR, GLUT1, GLUT3) as well as corresponding promoter DNA methylation were determined in mediobasal hypothalamic brain slices (Nucleus infundibuli hypothalami). Although no significant changes in morphometric and metabolic parameters were detected, strongly decreased mRNA expression occurred in all candidate genes. Surprisingly, however, no relevant alterations were observed in respective promoter methylation. Conclusion Prenatal hyperglycemia induces strong changes in later hypothalamic expression of INSR, LEPR, GLUT1, and GLUT3 mRNA. While the chicken provides an interesting approach for developmental malprogramming, the classical expression regulation via promoter methylation was not observed here. This may be due to alternative/interacting brain mechanisms or the thus far under-explored bird epigenome. PMID:25811618

Ott, Raffael; Bogatyrev, Semen; Tzschentke, Barbara; Plagemann, Andreas

2015-01-01

68

ABERRANT PROMOTER METHYLATION OF MULTIPLE GENES IN SPUTUM FROM INDIVIDUALS EXPOSED TO SMOKY COAL EMISSIONS  

EPA Science Inventory

Aberrant methylation in the promoter region of cancer-related genes leads to gene transcriptional inactivation and plays an integral role in lung tumorigenesis. Recent studies demonstrated that promoter methylation was detected not only in lung tumors from patients with lung canc...

69

Comprehensive serial analysis of gene expression of the cervical transcriptome  

PubMed Central

Background More than half of the approximately 500,000 women diagnosed with cervical cancer worldwide each year will die from this disease. Investigation of genes expressed in precancer lesions compared to those expressed in normal cervical epithelium will yield insight into the early stages of disease. As such, establishing a baseline from which to compare to, is critical in elucidating the abnormal biology of disease. In this study we examine the normal cervical tissue transcriptome and investigate the similarities and differences in relation to CIN III by Long-SAGE (L-SAGE). Results We have sequenced 691,390 tags from four L-SAGE libraries increasing the existing gene expression data on cervical tissue by 20 fold. One-hundred and eighteen unique tags were highly expressed in normal cervical tissue and 107 of them mapped to unique genes, most belong to the ribosomal, calcium-binding and keratinizing gene families. We assessed these genes for aberrant expression in CIN III and five genes showed altered expression. In addition, we have identified twelve unique HPV 16 SAGE tags in the CIN III libraries absent in the normal libraries. Conclusion Establishing a baseline of gene expression in normal cervical tissue is key for identifying changes in cancer. We demonstrate the utility of this baseline data by identifying genes with aberrant expression in CIN III when compared to normal tissue. PMID:17543121

Shadeo, Ashleen; Chari, Raj; Vatcher, Greg; Campbell, Jennifer; Lonergan, Kim M; Matisic, Jasenka; van Niekerk, Dirk; Ehlen, Thomas; Miller, Dianne; Follen, Michele; Lam, Wan L; MacAulay, Calum

2007-01-01

70

Comparison of methods to identify aberrant expression patterns in individual patients: augmenting our toolkit for precision medicine  

PubMed Central

Background Patient-specific aberrant expression patterns in conjunction with functional screening assays can guide elucidation of the cancer genome architecture and identification of therapeutic targets. Since most statistical methods for expression analysis are focused on differences between experimental groups, the performance of approaches for patient-specific expression analyses are currently less well characterized. A comparison of methods for the identification of genes that are dysregulated relative to a single sample in a given set of experimental samples, to our knowledge, has not been performed. Methods We systematically evaluated several methods including variations on the nearest neighbor based outlying degree method, as well as the Zscore and a robust variant for their suitability to detect patient-specific events. The methods were assessed using both simulations and expression data from a cohort of pediatric acute B lymphoblastic leukemia patients. Results We first assessed power and false discovery rates using simulations and found that even under optimal conditions, high effect sizes (>4 unit differences) were necessary to have acceptable power for any method (>0.9) though high false discovery rates (>0.1) were pervasive across simulation conditions. Next we introduced a technical factor into the simulation and found that performance was reduced for all methods and that using weights with the outlying degree could provide performance gains depending on the number of samples and genes affected by the technical factor. In our use case that highlights the integration of functional assays and aberrant expression in a patient cohort (the identification of gene dysregulation events associated with the targets from a siRNA screen), we demonstrated that both the outlying degree and the Zscore can successfully identify genes dysregulated in one patient sample. However, only the outlying degree can identify genes dysregulated across several patient samples. Conclusion Our results show that outlying degree methods may be a useful alternative to the Zscore or Rscore in a personalized medicine context especially in small to medium sized (between 10 and 50 samples) expression datasets with moderate to high sample-to-sample variability. From these results we provide guidelines for detection of aberrant expression in a precision medicine context. PMID:24286512

2013-01-01

71

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.  

PubMed

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps. PMID:25419707

Davis, Hayley; Irshad, Shazia; Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc C; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen J; Greten, Florian R; Wang, Lai Mun; East, James E; Tomlinson, Ian; Leedham, Simon J

2015-01-01

72

(gene expression) DNA (DNA microarrays).  

E-print Network

µ µ DNA . , µ . , µ . , . µ µµ µ µ (gene expression) . µ, µ µ DNA µ 100%. I. µ , µ [1]. µ µµ µ µ (gene expression. [2] M. K. Deyholos, and D. W. Galbraith, "High- Density Microarrays for Gene Expression Analysis

Athens, University of

73

Methylation of tumor suppressor genes is related with copy number aberrations in breast cancer  

PubMed Central

This study investigates the relationship of promoter methylation in tumor suppressor genes with copy-number aberrations (CNA) and with tumor markers in breast cancer (BCs). The study includes 98 formalin fixed paraffin-embedded BCs in which promoter methylation of 24 tumour suppressor genes were assessed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), CNA of 20 BC related genes by MLPA and ER, PR, HER2, CK5/6, CK18, EGFR, Cadherin-E, P53, Ki-67 and PARP expression by immunohistochemistry (IHC). Cluster analysis classed BCs in two groups according to promoter methylation percentage: the highly-methylated group (16 BCs), containing mostly hyper-methylated genes, and the sparsely-methylated group (82 BCs) with hypo-methylated genes. ATM, CDKN2A, VHL, CHFR and CDKN2B showed the greatest differences in the mean methylation percentage between these groups. We found no relationship of the IHC parameters or pathological features with methylation status, except for Catherin-E (p = 0.008). However the highly methylated BCs showed higher CNA proportion than the sparsely methylated BCs (p < 0.001, OR = 1.62; IC 95% [1.26, 2.07]). CDC6, MAPT, MED1, PRMD14 and AURKA showed the major differences in the CNA percentage between the two groups, exceeding the 22%. Methylation in RASSF1, CASP8, DAPK1 and GSTP1 conferred the highest probability of harboring CNA. Our results show a new link between promoter methylation and CNA giving support to the importance of methylation events to establish new BCs subtypes. Our findings may be also of relevance in personalized therapy assessment, which could benefit the hyper methylated BC patients group. PMID:25628946

Murria, Rosa; Palanca, Sarai; de Juan, Inmaculada; Egoavil, Cecilia; Alenda, Cristina; García-Casado, Zaida; Juan, María J; Sánchez, Ana B; Santaballa, Ana; Chirivella, Isabel; Segura, Ángel; Hervás, David; Llop, Marta; Barragán, Eva; Bolufer, Pascual

2015-01-01

74

Cross-talk between DNA methylation and active histone modifications regulates aberrant expression of ZAP70 in CLL  

PubMed Central

Zeta-associated protein of 70 kD (ZAP70) is a recognized adverse prognostic marker in chronic lymphocytic leukaemia (CLL) associated with enhanced B-cell receptor signalling, significantly more aggressive disease course and poor overall survival. Zeta-associated protein of 70 kD is ordinarily expressed in T cells where it has a crucial role in T-cell receptor signalling, whereas its aberrant expression in CLL leads to enhanced B-cell receptor signalling and significantly more aggressive disease course. Although much is known about the activation of ZAP70 following engagement of T-cell receptor, there are little data on the regulation of ZAP70 gene expression in normal T cells or CLL. To understand the molecular events underpinning epigenetic regulation of ZAP70 gene in CLL, we have defined ZAP70 promoter region and outlined the regions crucial in regulating the gene activity. Following a direct comparison of ZAP70+ and ZAP70? primary CLLs, we show ZAP70 promoter in expressing CLLs to be associated with a spectrum of active histone modifications, some of which are tightly linked to aberrant DNA methylation in CLL. Cross-talk between histone modifications and reduced DNA methylation culminates in transcriptional de-repression of ZAP70. Moreover, treatment with histone deacetylase (HDAC) and DNA methylation inhibitors results in recovery of ZAP70 expression, which provides a possible explanation for the failure of HDAC inhibitors in CLL treatment and might serve as a cautionary warning for their future use in treatment of this leukaemia. PMID:22151263

Amin, Shilu; Walsh, Meagan; Wilson, Caroline; Parker, Anton E; Oscier, David; Willmore, Elaine; Mann, Derek; Mann, Jelena

2012-01-01

75

Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens  

Microsoft Academic Search

Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant promoter methylation may play an important role in cancer development and progression. The purpose of this investigation was to determine the commonality for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyr- idyl)-1-butanone (NNK) and vinyl carbamate,

Leah C. Pulling; Brian R. Vuillemenot; Julie A. Hutt; Theodora R. Devereux; Steven A. Belinsky

2004-01-01

76

Association of a d-Alanyl-d-Alanine Carboxypeptidase Gene with the Formation of Aberrantly Shaped Cells during the Induction of Viable but Nonculturable Vibrio parahaemolyticus  

PubMed Central

Vibrio parahaemolyticus is a halophilic Gram-negative bacterium that causes human gastroenteritis. When the viable but nonculturable (VBNC) state of this bacterium was induced by incubation at 4°C in Morita minimal salt solution containing 0.5% NaCl, the rod-shaped cells became coccoid, and various aberrantly shaped intermediates were formed in the initial stage. This study examined the factors that influence the formation of these aberrantly shaped cells. The proportion of aberrantly shaped cells was not affected in a medium containing d-cycloserine (50 ?g/ml) but was lower in a medium containing cephalosporin C (10 ?g/ml) than in the control medium without antibiotics. The proportion of aberrantly shaped cells was higher in a culture medium that contained 0.5% NaCl than in culture media containing 1.0 or 1.5% NaCl. The expression of 15 of 17 selected genes associated with cell wall synthesis was enhanced, and the expression of VP2468 (dacB), which encodes d-alanyl-d-alanine carboxypeptidase, was enhanced the most. The proportion of aberrantly shaped cells was significantly lower in the dacB mutant strain than in the parent strain, but the proportion was restored in the presence of the complementary dacB gene. This study suggests that disturbance of the dynamics of cell wall synthesis by enhanced expression of the VP2468 gene is associated with the formation of aberrantly shaped cells in the initial stage of induction of VBNC V. parahaemolyticus cells under specific conditions. PMID:24056454

Hung, Wei-cheng; Jane, Wann-Neng

2013-01-01

77

SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers  

PubMed Central

We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify genes that would be aberrantly methylated at high frequency in human colon cancer. From among 1,231 genomic NotI sites assayed, site 3D41 was identified as methylated in 11 of 12 colon cancers profiled. Site 3D41 mapped to exon 1 of SLC5A8, a transcript that we assembled. In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed. In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines. SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine. Transfection of SLC5A8 suppressed colony growth in each of three SLC5A8-deficient cell lines, but showed no suppressive effect in any of three SLC5A8-proficient cell lines. SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci. Structural homology and functional testing demonstrated that SLC5A8 is a member of the family of sodium solute symporters, which are now added as a class of candidate colon cancer suppressor genes. PMID:12829793

Li, Hui; Myeroff, Lois; Smiraglia, Dominic; Romero, Michael F.; Pretlow, Theresa P.; Kasturi, Lakshmi; Lutterbaugh, James; Rerko, Ronald M.; Casey, Graham; Issa, Jean-Pierre; Willis, Joseph; Willson, James K. V.; Plass, Christoph; Markowitz, Sanford D.

2003-01-01

78

Aberrant expression of microRNA in polycythemia vera  

Microsoft Academic Search

Background Polycythemia vera is a clonal hematopoietic stem cell disorder in which the JAK2 V617F muta- tion is observed in >95% of patients, but an as yet unidentified process appears to initiate the clonal expansion of hematopoiesis. Because microRNA regulate hematopoietic differentiation, we hypothesized that dysregulated expression of microRNA may contribute to the pathophysi- ology of polycythemia vera. Design and

Hana Bruchova; Michaela Merkerova; Josef T. Prchal

2008-01-01

79

Identification of suitable endogenous control genes for microRNA gene expression analysis in human breast cancer  

Microsoft Academic Search

The discovery of microRNAs (miRNAs) added an extra level of intricacy to the already complex system regulating gene expression. These single-stranded RNA molecules, 18–25 nucleotides in length, negatively regulate gene expression through translational inhibition or mRNA cleavage. The discovery that aberrant expression of specific miRNAs contributes to human disease has fueled much interest in profiling the expression of these molecules.

Pamela A Davoren; Roisin E McNeill; Aoife J Lowery; Michael J Kerin; Nicola Miller

2008-01-01

80

Integrated analysis of genome-wide DNA methylation and gene expression profiles in  

E-print Network

Integrated analysis of genome-wide DNA methylation and gene expression profiles in molecular 15, 2013; Accepted July 2, 2013 ABSTRACT Aberrant DNA methylation of CpG islands, CpG island shores. To date, a systematic study on the effect of DNA methylation on gene expression using high resolution data

81

Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD  

PubMed Central

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-?3,?3,?2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-?2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD. PMID:24370592

Dang, Suparna; Marinkovich, M. Peter; Lazarova, Zelmira; Yoder, Bradley; Torres, Vicente E.; Wallace, Darren P.

2013-01-01

82

Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD.  

PubMed

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-?3,?3,?2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-?2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD. PMID:24370592

Vijayakumar, Soundarapandian; Dang, Suparna; Marinkovich, M Peter; Lazarova, Zelmira; Yoder, Bradley; Torres, Vicente E; Wallace, Darren P

2014-03-15

83

Evolutionary Genomics of Gene Expression  

NASA Astrophysics Data System (ADS)

The study of evolution at the molecular level has focused primarily on changes in gene (protein) sequences overtime [1]. Of course, phenotype is influenced not only by the sequence of genes but also by their expression patterns, i.e., the amplitude, timing, and spatial distribution of transcription. Thus, changes in gene expression are quite likely to be equally as important as sequence changes in evolution; indeed, the significance of gene expression divergence to the evolutionary process has been recognized for some time [2-4]. However, gene expression data have only recently accumulated to the levels needed for systematic evolutionary studies. This has been due to the application of new high-throughput techniques that measure gene expression levels for thousands of genes simultaneously [5-7], as well as the development of database resources needed to handle such data [8-10]. The availability of these expression data, together with the long standing interest in the evolutionary significance of gene expression, has stimulated numerous recent studies on gene expression divergence.

Jordan, I. King; Marińno-Ramírez, Leonardo

84

Natural selection on gene expression  

Microsoft Academic Search

Changes in genetic regulation contribute to adaptations in natural populations and influence susceptibility to human diseases. Despite their potential phenotypic importance, the selective pressures acting on regulatory processes in general and gene expression levels in particular are largely unknown. Studies in model organisms suggest that the expression levels of most genes evolve under stabilizing selection, although a few are consistent

Yoav Gilad; Alicia Oshlack; Scott A. Rifkin

2006-01-01

85

Method of controlling gene expression  

DOEpatents

A method of controlling expression of a DNA segment under the control of a nod gene promoter which comprises administering to a host containing a nod gene promoter an amount sufficient to control expression of the DNA segment of a compound of the formula: ##STR1## in which each R is independently H or OH, is described.

Peters, Norman K. (Berkeley, CA); Frost, John W. (Menlo Park, CA); Long, Sharon R. (Palo Alto, CA)

1991-12-03

86

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers.  

PubMed

Aberrant methylation of 5'gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n = 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon. PMID:16108009

Takahashi, Takao; Shigematsu, Hisayuki; Shivapurkar, Narayan; Reddy, Jyotsna; Zheng, Yingye; Feng, Ziding; Suzuki, Makoto; Nomura, Masaharu; Augustus, Meena; Yin, Jing; Meltzer, Stephen J; Gazdar, Adi F

2006-02-15

87

Gene expression and fractionation resistance  

PubMed Central

Background Previous work on whole genome doubling in plants established the importance of gene functional category in provoking or suppressing duplicate gene loss, or fractionation. Other studies, particularly in Paramecium have correlated levels of gene expression with vulnerability or resistance to duplicate loss. Results Here we analyze the simultaneous effect of function category and expression in two plant data sets, rosids and asterids. Conclusion We demonstrate function category and expression level have independent effects, though expression does not play the dominant role it does in Paramecium. PMID:25573431

2014-01-01

88

Aberrant immunoglobulin and c-myc gene rearrangements in patients with nonmalignant monoclonal cryoglobulinemia  

SciTech Connect

The status of the immunoglobulin (Ig) genes was investigated in patients with idiopathic nonmalignant monoclonal IgG cryoglobulinemia (NCG). In NCG, monoclonal antibodies are synthesized at an accelerated rate by nonmalignant B lymphocytes. In order to determine whether this high production rate is related to a clonal B cell expansion, the rearrangement of the Ig genes was investigated by Southern blot analysis of genomic, /sup 32/P-labelled, DNA extracted from the peripheral blood lymphocytes of four NCG patients. In three of four (VI, BR, and CH) clonal expansion of B cells was detected using probes specific for the genes. BamHI digestion of DNA from VI and BR produced three rearranged fragments which cohybridized with two of the probes. This finding suggested the presence of additional nonsecretory B cell clones and/or disruption of the gene segments spanned by and detected with the probes. In addition, the possibility of aberrant gene rearrangements was supported by noting the alteration of the c-myc gene locus in genomic DNA from peripheral blood leukocytes of VI and CH. Northern blot analysis of RNA isolated from peripheral blood B cells of VI and CH demonstrated aberrant transcripts of the c-myc gene, showing an active role of the altered c-myc locus. Detection of c-myc rearrangement in NCG patients clearly shows that this event may not be a final step in malignant B cell transformation.

Perl, A.; Wang, N.; Williams, J.M.; Hunt, M.J.; Rosenfeld, S.I.; Condemi, J.J.; Packman, C.H.; Abraham, G.N.

1987-11-15

89

Gene Expression-Based Classification  

Microsoft Academic Search

Recently, there has been a growing interest in classification of patient samples based on gene expressions. Here the classification task is made more difficult by the noisy nature of the data, and by the overwhelming number of genes relative to the number of available training samples in the data set. Moreover, many of these genes are irrelevant for classification and

Topon K. Paul; Hitoshi Iba

90

Aberrant SOX2 expression in colorectal cancers does not correlate with mucinous differentiation and gastric mucin MUC5AC expression.  

PubMed

Colorectal cancer (CRC) can be divided into non-mucinous and mucinous subtypes, of which the latter portends to have a worse clinical prognosis. A previous study suggested a putative link between SOX2 expression observed selectively in mucinous CRC and the induction of the gastric mucin MUC5AC. In this study, we re-evaluated the expression behavior of SOX2, MUC5AC, and CDX2 in both types of CRC. We performed immunohistochemical analysis on 90 cases of non-mucinous CRCs, 57 cases of mucinous CRCs, and 15 case-matched normal intestinal mucosa. In contrast to the previously suggested link between SOX2 and mucinous CRC, we observe aberrant expression of SOX2 at equal levels in both subtypes. Fluorescence in situ hybridization (FISH) analysis shows that expression is not attributed to genomic amplification. While SOX2 and CDX2 are normally expressed in a reciprocal manner, SOX2-positive tumor cells co-express CDX2. Furthermore, we show that MUC5AC is expressed independently of SOX2. In conclusion, we show that aberrant SOX2 expression is specifically linked neither to mucinous CRCs nor to the induction of MUC5AC, in contrast to previous suggestions. PMID:25108707

Raghoebir, Lalini; Biermann, Katharina; Kempen, Marjon Buscop-van; Dubbink, Hendrikus J; Dinjens, Winand N M; Hersmus, Remko; Looijenga, Leendert H J; Bruno, Marco J; Tibboel, Dick; Rottier, Robbert J; Smits, Ron

2014-10-01

91

RNA splicing mutation in an aberrantly rearranged immunoglobulin lambda I gene.  

PubMed Central

The mouse cell line MOPC 315 is an IgA (lambda II)-producing myeloma. We have studied a derivative of MOPC 315 that secretes normal lambda II chains but no heavy chain. This derivative, MOPC 315-26, was found to contain a rearranged lambda I gene in addition to a rearranged lambda II gene. The rearranged lambda I gene was cloned into bacteriophage lambda DNA and its structure was studied. The lambda I gene was found to have arisen by an aberrant recombination event that resulted in a single base insertion at the site of V-J region joining. In addition, the gene contained numerous point mutations in the vicinity of the junction of the V and J regions. Two point mutations occurred in the donor splice sequence normally used for the removal of the intron between the J and C regions, suggesting that the RNA synthesized from the aberrantly rearranged lambda I gene would be unable to undergo proper RNA splicing. Images PMID:6171827

Hozumi, N; Wu, G E; Murialdo, H; Roberts, L; Vetter, D; Fife, W L; Whiteley, M; Sadowski, P

1981-01-01

92

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.  

PubMed

Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the ?2? subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene. PMID:25074461

Vergult, Sarah; Dheedene, Annelies; Meurs, Alfred; Faes, Fran; Isidor, Bertrand; Janssens, Sandra; Gautier, Agnčs; Le Caignec, Cédric; Menten, Björn

2015-05-01

93

Alpharetroviral vector-mediated gene therapy for X-CGD: functional correction and lack of aberrant splicing.  

PubMed

Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model to evaluate the potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy of monogenic diseases. Therefore, we combined the alpharetroviral vector backbone with the elongation factor-1? short promoter, both considered to possess a low genotoxic profile, to drive transgene (gp91(phox)) expression. Following efficient transduction transgene expression was sustained and provided functional correction of the CGD phenotype in a cell line model at low vector copy number. Further analysis in a murine X-CGD transplantation model revealed gene-marking of bone marrow cells and oxidase positive granulocytes in peripheral blood. Transduction of human X-CGD CD34+ cells provided functional correction up to wild-type levels and long-term expression upon transplantation into a humanized mouse model. In contrast to lentiviral vectors, no aberrantly spliced transcripts containing cellular exons fused to alpharetroviral sequences were found in transduced cells, implying that the safety profile of alpharetroviral vectors may extend beyond their neutral integration profile. Taken together, this highlights the potential of this SIN alpharetroviral system as a platform for new candidate vectors for future gene therapy of hematopoietic disorders. PMID:23207695

Kaufmann, Kerstin B; Brendel, Christian; Suerth, Julia D; Mueller-Kuller, Uta; Chen-Wichmann, Linping; Schwäble, Joachim; Pahujani, Shweta; Kunkel, Hana; Schambach, Axel; Baum, Christopher; Grez, Manuel

2013-03-01

94

Aberrant phenotypic expression of CD15 and CD56 identifies poor prognostic acute promyelocytic leukemia patients.  

PubMed

Limited information is available on the relationship between expression of some additional aberrant phenotypic features and outcome of acute promyelocytic leukemia (APL) patients. Here, we set out to assess the frequency of CD15 and CD56 expression, and their prognostic value in a large series of APL patients. One hundred and fourteen adult patients consecutively diagnosed with PML/RAR?-positive APL and homogeneously treated with the AIDA induction schedule at a single institution were included in the study. Twelve (10.5%) and 9 (8%) of the 114 patients expressed CD15 and CD56, respectively. CD15 expression identified a subset of patients with a classic morphologic subtype (92%), a prevalent association with a bcr1 expression (67%) with an unexpectedly higher frequency of relapses (42% vs 20% for the CD15- patients, p=0.03) and a low overall survival (OS) (median OS at 5 years 58% vs 85% for the CD15- patients, p=0.01). CD56 expression was detected only in patients with a classic morphologic subtype, a prevalent bcr3 expression (67%), high incidence of differentiation syndrome (55%), higher frequency of relapse (34% vs 20% for the CD56- population, p=0.04) and a low OS (60% vs 85% for the CD56- population p=0.02). We hereby confirm the negative prognostic value of CD56 and we show that the same applies also to cases expressing CD15. These aberrant markers may be considered for the refinement of risk-adapted therapeutic strategies in APL patients. PMID:24296270

Breccia, Massimo; De Propris, Maria Stefania; Minotti, Clara; Stefanizzi, Caterina; Raponi, Sara; Colafigli, Gioia; Latagliata, Roberto; Guarini, Anna; Foŕ, Robin

2014-02-01

95

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer  

Microsoft Academic Search

BACKGROUND: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. RESULTS: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81

Eike Staub; Jörn Gröne; Detlev Mennerich; Stefan Röpcke; Irina Klamann; Bernd Hinzmann; Esmeralda Castanos-Velez; Benno Mann; Christian Pilarsky; Thomas Brümmendorf; Birgit Weber; Heinz-Johannes Buhr; André Rosenthal

2006-01-01

96

Clinical significance of mismatch repair gene expression in sporadic colorectal cancer  

PubMed Central

Mismatch repair (MMR) genes play an important role in the occurrence and development of sporadic colorectal cancer; however, the effect of MMR genes on clinicopathological features and prognosis remains unclear. The aim of the present study was to observe the clinical significance of MMR gene expression in sporadic colorectal cancer. Clinicopathological data and postoperative samples from 404 patients with sporadic colorectal cancer were obtained from the Affiliated Tumor Hospital of Xinjiang Medical University. The immunohistochemistry PV-9000 two-step method was performed to measure the protein expression of human mutL homolog 1 (hMLH1), human mutS homolog (hMSH) 2, human postmeiotic segregation increased 2 (hPSM2) and hMSH6. Differences in clinicopathological features, family history and survival time subsequent to surgery between groups with normal and aberrant MMR protein (MMRP) expression were compared. A total of 27.23% of all patients showed aberrant nuclear staining of MMRP. Among the patients with aberrant MMRP expression, a higher proportion of patients showed aberrant expression of more than one type of MMRP than aberrant expression of only one type of MMRP. Aberrant expression of hMLH1/hPSM2 was most commonly observed (29/404). In addition, aberrant MMRP expression in colorectal cancer was indicated predominantly in the right hemicolon. Histological type primarily showed mucinous adenocarcinoma. In addition, with increasing body mass index (BMI), the MMRP deficiency rate was also shown to increase gradually. There was a close association between MMRP expression deficiency and family history of cancer (P<0.05). For TNM stage III patients, the Kaplan-Meier survival curve showed that the aberrant MMRP expression group had a three-year disease-free survival (DFS) rate of 66.67%, which was longer than the DFS rate of the normal group (55.41%), with no statistical difference (P>0.05). In conclusion, the immunohistochemistry PV-9000 two-step method can be used to measure MMRP expression in colorectal cancer. Aberrant MMRP expression is closely correlated with tumor location, histological type, BMI and tumor family history in sporadic colorectal cancer. Aberrant MMRP expression may have an effect on the prognosis of stage III patients. PMID:25289032

SUN, ZHENQIANG; YU, XIANBO; WANG, HAIJIANG; ZHANG, SHUO; ZHAO, ZELIANG; XU, RUIWEI

2014-01-01

97

Revisiting Global Gene Expression Analysis  

E-print Network

Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other purposes. Recent studies indicate ...

Lovén, Jakob

98

Nuclear Neighborhoods and Gene Expression  

PubMed Central

Summary The eukaryotic nucleus is a highly compartmentalized and dynamic environment. Chromosome territories are arranged non-randomly within the nucleus and numerous studies have indicated that a gene’s position in the nucleus can impact its transcriptional activity. Here, we focus on recent advances in our understanding of the influence of specific nuclear neighborhoods on gene expression or repression. Nuclear neighborhoods associated with transcriptional repression include the inner nuclear membrane/nuclear lamina and peri-nucleolar chromatin, whereas neighborhoods surrounding the nuclear pore complex, PML nuclear bodies, and nuclear speckles seem to be transcriptionally permissive. While nuclear position appears to play an important role in gene expression, it is likely to be only one piece of a flexible puzzle that incorporates numerous parameters. We are still at a very early, yet exciting stage in our journey toward deciphering the mechanism(s) that govern the permissiveness of gene expression/repression within different nuclear neighborhoods. PMID:19339170

Zhao, Rui; Bodnar, Megan S.; Spector, David L.

2009-01-01

99

Regulation of Neuronal Gene Expression  

NASA Astrophysics Data System (ADS)

Humans as multicellular organisms contain a variety of different cell types where each cell population must fulfill a distinct function in the interest of the whole organism. The molecular basis for the variations in morphology, biochemistry, molecular biology, and function of the various cell types is the cell-type specific expression of genes. These genes encode proteins necessary for executing the specialized functions of each cell type within an organism. We describe here a regulatory mechanism for the expression of neuronal genes. The zinc finger protein REST binds to the regulatory region of many neuronal genes and represses neuronal gene expression in nonneuronal tissues. A negative regulatory mechanism, involving a transcriptional repressor, seems to play an important role in establishing the neuronal phenotype.

Thiel, Gerald; Lietz, Michael; Leichter, Michael

100

Book Review: Plant Gene Expression  

NSDL National Science Digital Library

Whereas many important biological discoveries have been made using plants, subsequent progress in some areas of plant research has fallen behind that in other organisms for which funding and in vitro assays are more readily available. Gene expression is one such field in which importance continues to grow because many potential plant biotechnology–based solutions to global problems depend on regulating the expression of specific genes. Previous limitations to exploring gene expression in plants have been partially mitigated by recent advances in genomics, genetics, and transformation techniques. The book Regulation of Gene Expression in Plants: The Role of Transcript Structure and Processing, edited by Carole L. Bassett, summarizes our current understanding of plant gene expression, with an emphasis on transcriptional and posttranscriptional regulation. The topics covered in six chapters include differences in messenger RNA (mRNA) structure caused by variations in transcription start and polyadenylation sites, alternative splicing, regulation by small RNAs, and mRNA transport and degradation. The chapters vary in depth, quality, and the degree to which the emphasis is placed on plants rather than eukaryotes in general. However, this slim volume is a useful review of gene expression in plants. The question of whether or not all differences in mRNA structure have functional importance remains open.

Alan Rose (University of California Davis; Molecular and Cellular Biology REV)

2007-05-22

101

Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes.  

PubMed

Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C P; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J; Boultwood, Jacqueline

2015-01-01

102

Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes  

PubMed Central

Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20–65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C. P.; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J.; Boultwood, Jacqueline

2015-01-01

103

Skeletrophin, a Novel Ubiquitin Ligase to the Intracellular Region of Jagged-2, Is Aberrantly Expressed in Multiple Myeloma  

PubMed Central

Recent research has indicated that ligand-dependent activation of the Notch receptor in stromal cells plays a crucial role in the tumorigenesis of multiple myeloma. Ubiquitination of intracellular regions of Notch receptor and its ligands is important for Notch signal transduction. In vitro autoubiquitination analysis using recombinant proteins identified skeletrophin as a novel RING finger-dependent ubiquitin ligase. Skeletrophin bound the intracellular regions of the Notch ligand Jagged-2, but not to those of Delta-1, -3, -4, or Jagged-1. Skeletrophin, but not its RING-mutated form, ubiquitinized the intracellular region of Jagged-2. In malignant plasma cells from 23 of 40 multiple myeloma specimens, strong skeletrophin expression was observed, especially from patients with osteolytic bone lesions. Cytoplasmic localization, which may indicate Jagged-2 internalization, was found in many skeletrophin-positive myeloma cells. In contrast, skeletrophin was only weakly expressed in a few nonneoplasmic plasma cells in chronically inflamed tissues. Interestingly, exogenous expression of skeletrophin, but not the RING-mutated form, in Jagged-2-positive P3U1 myeloma cells induced Hes-1 (Hairy and Enhancer of Split homolog-1) gene expression in Notch receptor-positive bone marrow stromal cells through direct cell-cell contact. Thus, skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells, possibly activating Hes-1 on stromal cells through ligand-dependent Notch signaling. PMID:15920166

Takeuchi, Tamotsu; Adachi, Yoshihiro; Ohtsuki, Yuji

2005-01-01

104

Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma.  

PubMed

Recent research has indicated that ligand-dependent activation of the Notch receptor in stromal cells plays a crucial role in the tumorigenesis of multiple myeloma. Ubiquitination of intracellular regions of Notch receptor and its ligands is important for Notch signal transduction. In vitro autoubiquitination analysis using recombinant proteins identified skeletrophin as a novel RING finger-dependent ubiquitin ligase. Skeletrophin bound the intracellular regions of the Notch ligand Jagged-2, but not to those of Delta-1, -3, -4, or Jagged-1. Skeletrophin, but not its RING-mutated form, ubiquitinized the intracellular region of Jagged-2. In malignant plasma cells from 23 of 40 multiple myeloma specimens, strong skeletrophin expression was observed, especially from patients with osteolytic bone lesions. Cytoplasmic localization, which may indicate Jagged-2 internalization, was found in many skeletrophin-positive myeloma cells. In contrast, skeletrophin was only weakly expressed in a few nonneoplasmic plasma cells in chronically inflamed tissues. Interestingly, exogenous expression of skeletrophin, but not the RING-mutated form, in Jagged-2-positive P3U1 myeloma cells induced Hes-1 (Hairy and Enhancer of Split homolog-1) gene expression in Notch receptor-positive bone marrow stromal cells through direct cell-cell contact. Thus, skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells, possibly activating Hes-1 on stromal cells through ligand-dependent Notch signaling. PMID:15920166

Takeuchi, Tamotsu; Adachi, Yoshihiro; Ohtsuki, Yuji

2005-06-01

105

Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: Mechanism, function, and implication for a potential novel therapeutic target  

PubMed Central

Treatment for high-risk pediatric and adult acute B cell lymphoblastic leukemia (B-ALL) remains challenging. Exploring novel pathways in B-ALL could lead to new therapy. Our previous study has shown that stem cell factor SALL4 is aberrantly expressed in B-ALL, but its functional roles and the mechanism that accounts for its upregulation in B-ALL remain unexplored. To address this question, we first surveyed the existing B-ALL cell lines and primary patient samples for SALL4 expression. We then selected the B-ALL cell lines with the highest SALL4 expression for functional studies. RNA interference was used to downregulate SALL4 expression in these cell lines. When compared with control cells, SALL4 knockdown cells exhibited decreased cell proliferation, increased apoptosis in vitro, and decreased engraftment in a xenotransplant model in vivo. Gene expression analysis showed that in SALL4 knockdown B-ALL cells, multiple caspase members involved in cell apoptosis pathway were upregulated. Next, we explored the mechanisms of aberrant SALL4 expression in B-ALL. We found that hypomethylation of the SALL4 CpG islands was correlated with its high expression. Furthermore, treatment of low SALL4-expressing B-ALL cell lines with DNA methylation inhibitor led to demethylation of the SALL4 CpG and increased SALL4 expression. In summary, to our knowledge, we are the first to show that the aberrant expression of SALL4 in B-ALL is associated with hypomethylation, and that SALL4 plays a key role in B-ALL cell survival and could be a potential novel target in B-ALL treatment. PMID:24463278

Ueno, Shikiko; Lu, Jiayun; He, Jie; Li, Ailing; Zhang, XiaoXian; Ritz, Jerome; Silberstein, Leslie E.; Chai, Li

2014-01-01

106

Aberrant expressions of delta-protocadherins in the brain of Npc1 mutant mice.  

PubMed

Niemann-Pick type C1 (NPC1) disease is an autosomal recessive disorder characterized by dysmyelination and neurodegeneration, which can result in the death of patients in early childhood in some cases. Members of the delta-protocadherins (Pcdhs) play important roles in neurogenesis and brain development. In this study, we compared expression profiles of Pcdhs in the brain of both wild-type and Npc1 mutant mice from postnatal day (P) 9 onwards by in situ hybridization. Our data show that laminar distribution of some Pcdhs in the cerebral cortex of Npc1 mutated mice is different from that of wild-type mice. Furthermore, expressions of Pcdhs by oligodendrocytes in the corpus callosum and by Purkinje cells and granular cells in the cerebellum are strongly decreased in Npc1 mutated mice at later stages. Taken together, our data suggest that aberrant expression of Pcdhs is a pathological process accompanied by neurodegeneration in Npc1 mutant mice. PMID:24671883

Yan, Xin; Lukas, Jan; Lin, Juntang; Ernst, Mathias; Koczan, Dirk; Witt, Martin; Fuellen, Georg; Wree, Andreas; Rolfs, Arndt; Luo, Jiankai

2014-09-01

107

Association of Cigarette Smoking with Aberrant Methylation of the Tumor Suppressor Gene RAR?2 in Papillary Thyroid Cancer  

PubMed Central

Aberrant gene methylation is often seen in thyroid cancer, a common endocrine malignancy. Tobacco smoking has been shown to be associated with aberrant gene methylation in several cancers, but its relationship with gene methylation in thyroid cancer has not been examined. In the present study, we investigated the relationship between smoking of patients and aberrant methylation of tumor suppressor genes for TIMP3, SLC5A8, death-associated protein kinase, and retinoic acid receptor ?2 (RAR?2) in papillary thyroid cancer (PTC), the most common type of thyroid cancer. The promoter methylation status of these genes was analyzed using quantitative real-time methylation-specific PCR on bisulfite-treated genomic DNA isolated from tumor tissues and correlated with smoking history of the patients. Among the four genes, methylation of the RAR?2 gene was significantly associated with smoking and other three genes showed a trend of association. Specifically, among the 138 patients investigated, 13/42 (31.0%) ever smokers vs. 10/96 (10.4%) never smokers harbored methylation of the RAR?2 gene (P?=?0.003). This association was highly significant also in the subset of conventional variant PTC (P?=?0.005) and marginally significant in follicular variant PTC (P?=?0.06). The results demonstrate that smoking-associated aberrant methylation of the RAR?2 gene is a specific molecular event that may represent an important mechanism in thyroid tumorigenesis in smokers. PMID:22649395

Kiseljak-Vassiliades, Katja; Xing, Mingzhao

2011-01-01

108

Aberrant DNA methylation of MGMT and hMLH1 genes in prediction of gastric cancer.  

PubMed

We aimed to explore the association between aberrant DNA methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) and human mutL homolog 1 (hMLH1) genes with gastric cancer. A total of 283 gastric cancer patients who were confirmed by pathological diagnosis were included in our study. Aberrant DNA methylation of MGMT and hMLH1 were detected. The proportions of DNA hypermethylation in MGMT and hMLH1 in cancer tissues were significantly higher than those in remote normal-appearing tissues. The DNA hypermethylation of MGMT was correlated with the tumor-necrosis-metastasis stage in gastric cancer tissues. Results showed that individuals with gastric cancer in the N1 and M1 stages had a significantly higher risk of DNA hypermethylation of MGMT in cancer tissues [odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.15-3.37 for the N1 stage; OR (95%CI) = 5.39 (2.08-14.98) for the M1 stage]. In conclusion, we found that aberrant hypermethylation of MGMT could be a predictive biomarker for detecting gastric cancer. PMID:24938706

Jin, J; Xie, L; Xie, C H; Zhou, Y F

2014-01-01

109

Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy  

PubMed Central

Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMN?7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV. PMID:23630626

Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan; Price, Loren; Muntoni, Francesco; Fletcher, Sue; Wilton, Steve D.; Burghes, Arthur H. M.

2013-01-01

110

Aberrant Expression of Fetal RNA-Binding Protein p62 in Liver Cancer and Liver Cirrhosis  

PubMed Central

p62 is a RNA-binding protein that was isolated by immunoscreening a cDNA expression library with autoantibodies from patients with hepatocellular carcinoma (HCC). This autoantigen binds to mRNA encoding insulin-like growth factor II, which has been found to be overexpressed in HCC and is tumorigenic in transgenic animals. Immunohistochemical analysis of HCC liver showed that 33% (9 of 27) exhibited readily detectable staining of p62 protein in the cytoplasm of all malignant cells in cancer nodules, whereas it was undetectable in adjacent nonmalignant liver cells. In addition one of two patients with cholangiocarcinoma expressed p62 in malignant bile duct epithelial cells. p62 expression was also detected in scattered cells in cirrhotic nodules in contrast to uniform expression in all cells in HCC nodules. In HCC nodules, p62 mRNA was also detected by reverse transcriptase-polymerase chain reaction analysis. Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II. PMID:11549587

Lu, Maolong; Nakamura, Robert M.; Dent, E. DuBose; Zhang, Jian-Ying; Nielsen, Finn C.; Christiansen, Jan; Chan, Edward K. L.; Tan, Eng M.

2001-01-01

111

Using Gene Expression Noise to Understand Gene Regulation  

E-print Network

REVIEW Using Gene Expression Noise to Understand Gene Regulation Brian Munsky,1 * Gregor Neuert,2 environments display variable phenotypes. Stochastic gene expression, or gene expression "noise," has been and messenger RNA levels, and they have discovered strong connections between noise and gene regulation

Munsky, Brian

112

Extracting Knowledge from Dynamics in Gene Expression  

Microsoft Academic Search

Most investigations of coordinated gene expression have focused on year, the focus of the research community is shifting toward identifying correlated expression patterns between genes by examining a functional understanding of the roles of and relationships their normalized static expression levels. In this study, we focus on between different genes. With advances in genetic expres- the dynamics of gene expression

Ben Y. Reis; Atul J. Butte; Isaac S. Kohane

2001-01-01

113

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas  

PubMed Central

Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis. PMID:21514413

Campos, Benito; Centner, Franz-Simon; Bermejo, Justo Lorenzo; Ali, Ramadan; Dorsch, Katharina; Wan, Feng; Felsberg, Jörg; Ahmadi, Rezvan; Grabe, Niels; Reifenberger, Guido; Unterberg, Andreas; Burhenne, Jürgen; Herold-Mende, Christel

2011-01-01

114

Aberrant expression of retinoic acid signaling molecules influences patient survival in astrocytic gliomas.  

PubMed

Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis. PMID:21514413

Campos, Benito; Centner, Franz-Simon; Bermejo, Justo Lorenzo; Ali, Ramadan; Dorsch, Katharina; Wan, Feng; Felsberg, Jörg; Ahmadi, Rezvan; Grabe, Niels; Reifenberger, Guido; Unterberg, Andreas; Burhenne, Jürgen; Herold-Mende, Christel

2011-05-01

115

SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers  

Microsoft Academic Search

We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify

Hui Li; Lois Myeroff; Dominic Smiraglia; Michael F. Romero; Theresa P. Pretlow; Lakshmi Kasturi; James Lutterbaugh; Ronald M. Rerko; Graham Casey; Jean-Pierre Issa; Joseph Willis; James K. V. Willson; Christoph Plass; Sanford D. Markowitz

2003-01-01

116

Aberrant expression of maternal Plk1 and Dctn3 results in the developmental failure of human in-vivo- and in-vitro-matured oocytes  

PubMed Central

Fertilisation is the first step in embryonic development, and dynamic changes of key genes may potentially improve assisted reproduction techniques efficiency during this process. Here, we analysed genes that were differentially expressed between oocytes and zygotes and focused on cytokinesis-related genes. Plk1 and Dctn3 were identified as showing dramatic changes in expression during fertilisation and were suggested to play a key role in inducing aneuploidy in zygotes and 8-cell embryos. Moreover, we found that maternal Plk1 and Dctn3 were expressed at lower levels in in vitro matured oocytes, which may have contributed to the high ratio of resulting embryos with abnormal Plk1 and Dctn3 expression levels, thereby reducing the developmental competence of the resulting embryos. Furthermore, the overexpression of Dctn3 can silence Plk1 expression, which suggests a potential regulation mechanism. In conclusion, our present study showed that aberrant expression of Plk1 and Dctn3 increases embryo aneuploidy and developmental failure, particularly in in vitro matured oocytes. Our results facilitate a better understanding of the effects of oocyte maternal gene expression on embryonic development and can be used to improve the outcome of assisted reproduction techniques. PMID:25645239

Fan, Yong; Zhao, Hong-Cui; Liu, Jianqiao; Tan, Tao; Ding, Ting; Li, Rong; Zhao, Yue; Yan, Jie; Sun, Xiaofang; Yu, Yang; Qiao, Jie

2015-01-01

117

Aberrant expression of maternal Plk1 and Dctn3 results in the developmental failure of human in-vivo- and in-vitro-matured oocytes.  

PubMed

Fertilisation is the first step in embryonic development, and dynamic changes of key genes may potentially improve assisted reproduction techniques efficiency during this process. Here, we analysed genes that were differentially expressed between oocytes and zygotes and focused on cytokinesis-related genes. Plk1 and Dctn3 were identified as showing dramatic changes in expression during fertilisation and were suggested to play a key role in inducing aneuploidy in zygotes and 8-cell embryos. Moreover, we found that maternal Plk1 and Dctn3 were expressed at lower levels in in vitro matured oocytes, which may have contributed to the high ratio of resulting embryos with abnormal Plk1 and Dctn3 expression levels, thereby reducing the developmental competence of the resulting embryos. Furthermore, the overexpression of Dctn3 can silence Plk1 expression, which suggests a potential regulation mechanism. In conclusion, our present study showed that aberrant expression of Plk1 and Dctn3 increases embryo aneuploidy and developmental failure, particularly in in vitro matured oocytes. Our results facilitate a better understanding of the effects of oocyte maternal gene expression on embryonic development and can be used to improve the outcome of assisted reproduction techniques. PMID:25645239

Fan, Yong; Zhao, Hong-Cui; Liu, Jianqiao; Tan, Tao; Ding, Ting; Li, Rong; Zhao, Yue; Yan, Jie; Sun, Xiaofang; Yu, Yang; Qiao, Jie

2015-01-01

118

Connectionist Approaches for Predicting Mouse Gene Function from Gene Expression  

E-print Network

Connectionist Approaches for Predicting Mouse Gene Function from Gene Expression Emad Andrews. emad@cs.toronto.edu Abstract. Identifying gene function has many useful applications especially in Gene Therapy. Identifying gene function based on gene expression data is much easier in prokaryotes than

Bonner, Anthony

119

Population genomics of human gene expression  

Microsoft Academic Search

Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus–transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression

Barbara E Stranger; Alexandra C Nica; Matthew S Forrest; Antigone Dimas; Christine P Bird; Claude Beazley; Catherine E Ingle; Mark Dunning; Paul Flicek; Daphne Koller; Stephen Montgomery; Simon Tavare ´; Panos Deloukas; Emmanouil T Dermitzakis

2007-01-01

120

Transgenic Arabidopsis Gene Expression System  

NASA Technical Reports Server (NTRS)

The Transgenic Arabidopsis Gene Expression System (TAGES) investigation is one in a pair of investigations that use the Advanced Biological Research System (ABRS) facility. TAGES uses Arabidopsis thaliana, thale cress, with sensor promoter-reporter gene constructs that render the plants as biomonitors (an organism used to determine the quality of the surrounding environment) of their environment using real-time nondestructive Green Fluorescent Protein (GFP) imagery and traditional postflight analyses.

Ferl, Robert; Paul, Anna-Lisa

2009-01-01

121

Autogenous regulation of gene expression.  

PubMed

A new term, autogenous regulation, is used to describe a phenomenon that is not a new discovery but rather is newly appreciated as a mechanism common to a number of systems in both prokaryotic and eukaryotic organisms. In this mechanism the product of a structural gene regulates expression of the operon in which that structural gene resides. In many (perhaps all) cases, the regulatory gene product has several functions, since it may act not only as a regulatory protein but also as an enzyme, structural protein, or antibody, for example. In a few cases, this protein is the multimeric allosteric enzyme that catalyzes the first step of a metabolic pathway, gearing together the two most important mechanisms for controlling the biosynthesis of metabolites in bacterial cells-feedback inhibition and repression. Autogenous regulation may provide a mechanism for amplification of gene expression (84); for severe and prolonged inactivation of gene expression (85); for buffering the response of structural genes to changes in the environment (45, 52); and for maintaining a constant intracellular concentration of a protein, independent of cell size or growth rate (86). Thus, autogenous regulation provides the cell with means for accomplishing a number of different regulatory tasks, each suited to better satisfying the needs of the organism for its survival. PMID:4589900

Goldberger, R F

1974-03-01

122

Clinical significance of aberrant mammalian target of rapamycin expression in stage IIIB colon cancer  

PubMed Central

The aim of the present study was to investigate the significance of aberrant expression of mammalian target of rapamycin (mTOR) and the activated form of mTOR kinase, phosphorylated mTOR (pmTOR), in human stage IIIB colon cancer. The expression of mTOR and pmTOR was detected by immunohistochemistry in the tumor tissue of stage IIIB colon cancer patients. The association between the expression of mTOR, pmTOR and clinicopathological parameters of patients was analyzed. The positive expression of mTOR and pmTOR was observed to be higher in 75.5% (80/106) and 76.4% (81/106) of the 106 colon cancer specimens, compared with the adjacent normal tissues. The high level of pmTOR expression was found to be significantly higher in the invasive tumor front cells and resulted in a higher risk of mortality. The results suggested that mTOR and pmTOR may be promising clinical markers and present novel molecular targets for designing novel therapeutic strategies to treat this malignancy. PMID:25120661

WEN, MEILING; LI, BAOXIU; CAO, XIAOFEI; WENG, CHENGYIN; WU, YONG; FANG, XISHENG; ZHANG, XIAOSHI; LIU, GUOLONG

2014-01-01

123

Overexpression of regenerating gene I? appears to reflect aberration of crypt cell compartmentalization in sessile serrated adenoma/polyps of the colon  

PubMed Central

Background Colorectal sessile serrated adenoma/polyps (SSA/Ps) are characterized by asymmetrical distribution of Ki67-positive cells, which varies among crypts and involves the crypt length to a variable extent; the pattern has been designated as aberration of crypt cell compartmentalization. The regenerating gene (REG) I? is a cell growth and/or anti-apoptotic factor and its overexpression might be associated with aberration of crypt cell compartmentalization in SSA/Ps. We investigated REG I? expression in SSA/Ps in comparison to hyperplastic polyps (HPs). Methods A total of 64 cases of serrated polyps (?10 mm in size), including 53 SSA/Ps and 11 HPs, were included in the present study. Immunostaining was performed using a labeled streptavidin-biotin method. REG I? expression was classified as follows: (i) expression of endocrine cells: grade 0 (a few positive cells) to 3 (marked increase in positive cells); (ii) expression of goblet cells: grade 0 (negative) to 2 (positive for crypts and surface epithelial cells); (iii) staining intensity of goblet cells: grade 0 (negative) to 2 (strong); (iv) staining intensity of crypt (absorptive) cell membranes: grade 0 (negative) to 2 (strong). The presence of aberration of crypt cell compartmentalization was assessed using Ki67 immunostaining. Results With regard to the REG I? expression of endocrine cells, 8 out of 11 HPs (73%) were grade 0, whereas 51 of 53 SSA/Ps (96%) were grade 1 or higher (p?Aberration of crypt cell compartmentalization was more frequently identified in SSA/Ps (72%) than in HPs (18%; p?=?0.002). A significant association was observed between REG I? overexpression and the aberration of crypt cell compartmentalization in serrated polyps (p?=?0.037). Conclusions REG I? overexpression is a characteristic of SSA/Ps, which appears to reflect aberration of crypt cell compartmentalization. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7240956081100040 PMID:24225137

2013-01-01

124

p53-Mediated Repression of Alpha-Fetoprotein Gene Expression by Specific DNA Binding  

Microsoft Academic Search

Aberrant expression of the alpha-fetoprotein (AFP) gene is characteristic of a majority of hepatocellular car- cinoma cases and serves as a diagnostic tumor-specific marker. By dissecting regulatory mechanisms through electromobility gel shift, transient-transfection, Western blot, and in vitro transcription analyses, we find that AFP gene expression is controlled in part by mutually exclusive binding of two trans-acting factors, p53 and

KATHLEEN C. LEE; ALISON J. CROWE; MICHELLE CRAIG BARTON

125

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia  

Microsoft Academic Search

Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at

Adolfo A. Ferrando; Donna S. Neuberg; Jane Staunton; Mignon L. Loh; Christine Huard; Susana C. Raimondi; Fred G. Behm; Ching-Hon Pui; James R. Downing; D. Gary Gilliland; Eric S. Lander; Todd R. Golub; A. Thomas Look

2002-01-01

126

Analysis of Microarray Gene Expression Data  

Microsoft Academic Search

Microarrays provide the biological research community with tremendously rich, sensitive and detailed information on gene expression profiles. Gene expression profiling and gene expression patterns have been found useful for solving a wide variety of important biological and biomedical problems, including the study of metabolic pathways, inference of the functions of unknown genes, diagnosis of diseased states, as well as facilitating

Tuan D. Pham; Christine Wells; Denis I. Crane

2006-01-01

127

Aberrant expression of Eag1 potassium channels in gastric cancer patients and cell lines.  

PubMed

Recently, an interesting relationship between potassium channels and cancer has evolved. The aim of this study is to investigate expression of Eag1 potassium channel in gastric cancer and its role in cancer cells growth. The expression of Eag1 for gasric cancer patients and cell lines as well as gastric adenoma was investigated by immunohistochemistry and reverse transcription polymerase chain reaction. In addition, imipramine was used to identify the involvement of Eag1 in the growth of SGC-7901 and BGC-823 cells. Frequency of positive expression of Eag1 protein was 70.5% (67/95) and Eag1 mRNA was 68.2% (15/22) in gastric cancer primary tissues. Eag1 mRNA was positively expressed in two gastric cell lines. Eag1 protein and mRNA were negatively expressed in paired non-cancerous matched tissues and 5 cases of adenoma tissues. The expression level of Eag1 protein was associated with lymph node metastasis (P = 0.049) and stage (P = 0.039), but had no correlation with sex, age, differentiation grades, and other organs metastases. Imipramine significantly inhibited the proliferation of SGC-7901 and BGC-823 cells at 12 h and 24 h detected by cells number counting and MTT assay (P < 0.01). The study indicates Eag1 is aberrantly expressed in gastric cancer tissues and cell lines and associated with cancer lymph node metastasis and stage and play an important role in the proliferation of gastric cancer cells. PMID:17873312

Ding, Xiang-Wu; Luo, He-sheng; Jin, Xiong; Yan, Juan-juan; Ai, Yao-wei

2007-01-01

128

Vascular gene expression: a hypothesis  

PubMed Central

The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a “primitive” vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants. PMID:23882276

Martínez-Navarro, Angélica C.; Galván-Gordillo, Santiago V.; Xoconostle-Cázares, Beatriz; Ruiz-Medrano, Roberto

2013-01-01

129

Regulators of gene expression as biomarkers for prostate cancer  

PubMed Central

Recent technological advancements in gene expression analysis have led to the discovery of a promising new group of prostate cancer (PCa) biomarkers that have the potential to influence diagnosis and the prediction of disease severity. The accumulation of deleterious changes in gene expression is a fundamental mechanism of prostate carcinogenesis. Aberrant gene expression can arise from changes in epigenetic regulation or mutation in the genome affecting either key regulatory elements or gene sequences themselves. At the epigenetic level, a myriad of abnormal histone modifications and changes in DNA methylation are found in PCa patients. In addition, many mutations in the genome have been associated with higher PCa risk. Finally, over- or underexpression of key genes involved in cell cycle regulation, apoptosis, cell adhesion and regulation of transcription has been observed. An interesting group of biomarkers are emerging from these studies which may prove more predictive than the standard prostate specific antigen (PSA) serum test. In this review, we discuss recent results in the field of gene expression analysis in PCa including the most promising biomarkers in the areas of epigenetics, genomics and the transcriptome, some of which are currently under investigation as clinical tests for early detection and better prognostic prediction of PCa. PMID:23226612

Willard, Stacey S; Koochekpour, Shahriar

2012-01-01

130

Gene Expression in Trypanosomatid Parasites  

PubMed Central

The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa. PMID:20169133

Martínez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C.; Florencio-Martínez, Luis E.; Manning-Cela, Rebeca G.; Figueroa-Angulo, Elisa E.

2010-01-01

131

Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer  

PubMed Central

Protein Phosphatase 2A (PP2A) is an important and ubiquitously expressed serine threonine phosphatase and regulates the function by dephosphorylating many critical cellular molecules like Akt, p53, c-Myc and ?-catenin. It plays a critical role in cellular processes, such as cell proliferation, signal transduction and apoptosis. Structurally, it is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. PP2A undergoes post-translational modifications (i.e. phosphorylation and methylation), which in turn, regulates its enzymatic activity. Aberrant expression, mutations and somatic alterations of the PP2A scaffold and regulatory subunits have been observed in various human malignancies, including lung, breast, skin and colon cancer, highlighting its role as a ‘tumor suppressor’. This review is focused on the structural complexity of serine/threonine phosphatase PP2A and summarizes its expression pattern in cancer. Additionally, the PP2A interacting and regulatory proteins and substrates are also discussed. Finally, the mouse models developed to understand the biological role of PP2A subunits in an in vivo model system are also reviewed in this article. PMID:23454242

Seshacharyulu, Parthasarathy; Pandey, Poomy; Datta, Kaustubh; Batra, Surinder K.

2013-01-01

132

Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease  

Microsoft Academic Search

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time,

Natalie A. Twine; Karolina Janitz; Marc R. Wilkins; Michal Janitz

2011-01-01

133

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

134

Maintenance of gene expression patterns.  

PubMed

In development, cells pass on established gene expression patterns to daughter cells over multiple rounds of cell division. The cellular memory of the gene expression state is termed maintenance, and the proteins required for this process are termed maintenance proteins. The best characterized are proteins of the Polycomb and trithorax Groups that are required for silencing and maintenance of activation of target loci, respectively. These proteins act through DNA elements termed maintenance elements. Here, we re-examine the genetics and molecular biology of maintenance proteins. We discuss molecular models for the maintenance of activation and silencing, and the establishment of epigenetic marks, and suggest that maintenance proteins may play a role in propagating the mark through DNA synthesis. PMID:15704101

Brock, Hugh W; Fisher, Cynthia L

2005-03-01

135

Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial–mesenchymal transition  

PubMed Central

The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial–mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease. PMID:25750173

Liu, Hong; Ren, Guoping; Wang, Tingyang; Chen, Yuexia; Gong, Chaoju; Bai, Yanfeng; Wang, Bo; Qi, Hongyan; Shen, Jing; Zhu, Lijun; Qian, Cheng; Lai, Maode; Shao, Jimin

2015-01-01

136

Gene expression profiling in single cells  

E-print Network

Gene expression profiling in single cells within tissue Paola Capodieci1, Michael Donovan1, Heidi the microanatomical context. This identifies single-cell gene expression patterns by probing multiple, unique nascent RNA transcripts and yields predictive quantitative gene expression signatures. Integrating

Cai, Long

137

Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes  

PubMed Central

We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets. PMID:25014031

Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie

2014-01-01

138

Identifying Gene Regulatory Networks from Gene Expression Data  

E-print Network

27 Identifying Gene Regulatory Networks from Gene Expression Data Vladimir Filkov University of California, Davis 27.1 Introduction................................ ........... 27-1 27.2 Gene Networks ............................ ........... 27-2 Definition · Biological Properties · Utility 27.3 Gene Expression: Data and Analysis

Filkov, Vladimir

139

Antisense expression increases gene expression variability and locus interdependency  

PubMed Central

Genome-wide transcription profiling has revealed extensive expression of non-coding RNAs antisense to genes, yet their functions, if any, remain to be understood. In this study, we perform a systematic analysis of sense–antisense expression in response to genetic and environmental changes in yeast. We find that antisense expression is associated with genes of larger expression variability. This is characterized by more ‘switching off' at low levels of expression for genes with antisense compared to genes without, yet similar expression at maximal induction. By disrupting antisense transcription, we demonstrate that antisense expression confers an on-off switch on gene regulation for the SUR7 gene. Consistent with this, genes that must respond in a switch-like manner, such as stress–response and environment-specific genes, are enriched for antisense expression. In addition, our data provide evidence that antisense expression initiated from bidirectional promoters enables the spreading of regulatory signals from one locus to neighbouring genes. These results indicate a general regulatory effect of antisense expression on sense genes and emphasize the importance of antisense-initiating regions downstream of genes in models of gene regulation. PMID:21326235

Xu, Zhenyu; Wei, Wu; Gagneur, Julien; Clauder-Münster, Sandra; Smolik, Mi?osz; Huber, Wolfgang; Steinmetz, Lars M

2011-01-01

140

RDX Induces Aberrant Expression of MicroRNAs in Mouse Brain and Liver  

PubMed Central

Background Although microRNAs (miRNAs) have been found to play an important role in many biological and metabolic processes, their functions in animal response to environmental toxicant exposure are largely unknown. Objectives We used hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a common environmental contaminant, as a toxicant stressor to investigate toxicant-induced changes in miRNA expression in B6C3F1 mice and the potential mechanism of RDX-induced toxic action. Methods B6C3F1 mice were fed diets with or without 5 mg/kg RDX for 28 days. After the feeding trials, we isolated RNAs from both brain and liver tissues and analyzed the expression profiles of 567 known mouse miRNAs using microarray and quantitative real-time polymerase chain reaction technologies. Results RDX exposure induced significant changes in miRNA expression profiles. A total of 113 miRNAs, belonging to 75 families, showed significantly altered expression patterns after RDX exposure. Of the 113 miRNAs, 10 were significantly up-regulated and 3 were significantly down-regulated (p < 0.01) in both mouse brain and liver. Many miRNAs had tissue-specific responses to RDX exposure. Specifically, expression of seven miRNAs was up-regulated in the brain but down-regulated in the liver or up-regulated in the liver but down-regulated in the brain (p < 0.01). Many aberrantly expressed miRNAs were related to various cancers, toxicant-metabolizing enzymes, and neurotoxicity. We found a significant up-regulation of oncogenic miRNAs and a significant down-regulation of tumor-suppressing miRNAs, which included let-7, miR-17-92, miR-10b, miR-15, miR-16, miR-26, and miR-181. Conclusions Environmental toxicant exposure alters the expression of a suite of miRNAs. PMID:19270793

Zhang, Baohong; Pan, Xiaoping

2009-01-01

141

Gene expression pattern A hierarchy of gene expression accompanying induction of the primitive  

E-print Network

Gene expression pattern A hierarchy of gene expression accompanying induction of the primitive the time-course of appearance and disappearance of expression of 12 genes (cVg1, Lef1, Nodal, FGF8, cWnt8C that a hierarchy of gene expression accompanies induction of the ectopic axis, reminiscent of the order in which

Stern, Claudio

142

GEO: the Gene Expression Omnibus A family of databases for gene expression related data  

E-print Network

GEO: the Gene Expression Omnibus A family of databases for gene expression related data http Contact: info@ncbi.nlm.nih.gov Scope and access The Gene Expression Omnibus (GEO) is a public repository databases, data and record types While GEO was originally established to host gene expression data, it has

Levin, Judith G.

143

Does inbreeding affect gene expression in birds?  

PubMed

Inbreeding increases homozygosity, exposes genome-wide recessive deleterious alleles and often reduces fitness. The physiological and reproductive consequences of inbreeding may be manifested already during gene regulation, but the degree to which inbreeding influences gene expression is unknown in most organisms, including in birds. To evaluate the pattern of inbreeding-affected gene expression over the genome and in relation to sex, we performed a transcriptome-wide gene expression (10 695 genes) study of brain tissue of 10-day-old inbred and outbred, male and female zebra finches. We found significantly lower gene expression in females compared with males at Z-linked genes, confirming that dosage compensation is incomplete in female birds. However, inbreeding did not affect gene expression at autosomal or sex-linked genes, neither in males nor in females. Analyses of single genes again found a clear sex-biased expression at Z-linked genes, whereas only a single gene was significantly affected by inbreeding. The weak effect of inbreeding on gene expression in zebra finches contrasts to the situation, for example, in Drosophila where inbreeding has been found to influence gene expression more generally and at stress-related genes in particular. PMID:25232028

Hansson, Bengt; Naurin, Sara; Hasselquist, Dennis

2014-09-01

144

DNA methylation and gene expression profiling of ewing sarcoma primary tumors reveal genes that are potential targets of epigenetic inactivation.  

PubMed

The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin-embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs) using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA)-treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1,) and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis. PMID:23024594

Patel, Nikul; Black, Jennifer; Chen, Xi; Marcondes, A Mario; Grady, William M; Lawlor, Elizabeth R; Borinstein, Scott C

2012-01-01

145

DNA Methylation and Gene Expression Profiling of Ewing Sarcoma Primary Tumors Reveal Genes That Are Potential Targets of Epigenetic Inactivation  

PubMed Central

The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin-embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs) using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA)-treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1,) and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis. PMID:23024594

Patel, Nikul; Black, Jennifer; Chen, Xi; Marcondes, A. Mario; Grady, William M.; Lawlor, Elizabeth R.; Borinstein, Scott C.

2012-01-01

146

Aberrant Expression of Beclin-1 and LC3 Correlates with Poor Prognosis of Human Hypopharyngeal Squamous Cell Carcinoma  

PubMed Central

Background Beclin-1, a key regulator of autophagy. Microtubule-associated protein 1 light chain 3 (LC3), is involved in autophagsome formation during autophagy. The autophagic genes beclin-1 and LC3 paly an important role in the development and progression of tumor. This study was designed to investigate the expression of beclin-1 and LC3 and to clarify their clinical significance in hypopharyngeal squamous cell carcinoma (HSCC). Methods Eighty-two surgical hypopharyngeal squamous cell carcinoma specimens and fifty-four adjacent non-cancerous mucosal epithelial tissues were obtained. Beclin-1 and LC3-II expression was examined by immunohistochemistry, real-time RT-PCR and Western blotting assays. Correlations with patient clinical characteristics and overall survival were evaluated. Results Beclin-1 was positively expressed in 42.7% (35/82) of HSCC specimens (adjacent non-cancerous tissues, 79.6%, 43/54; P<0.0001). Furthermore, 41.5% (34/82) of HSCC specimens exhibited high LC3 immunoreactivity (adjacent non-cancerous tissues, 74.1%, 40/54; P=0.0002). Beclin-1 and LC3-II mRNA transcript levels were significantly lower in HSCCs than in paired non-cancerous tissues (P<0.0001, P=0.0001, respectively). Similarly, western blotting assays showed that beclin-1 and LC3-II were markedly decreased in HSCCs (P=0.02, P=0.004, respectively). A positive correlation was observed between the mRNA transcript levels of beclin-1 and LC3-II in HSCCs (r=0.51, P<0.0001; 95%CI: 0.273 to 0.689). Beclin-1 and LC3 expression were significantly correlated with T categories, differentiation and lymph node metastasis. Negative beclin-1 immuoreactivity and low LC3 expression were associated with poorer overall survival in HSCC patients (P<0.0001, P=0.0145, respectively). Multivariate analysis revealed that beclin-1 was an independent prognositic factor for overall survival. Conclusion Beclin-1 and LC3-II are downregulated in HSCCs and their aberrant expression correlates with poor prognosis of HSCCs. PMID:23935917

Wang, Juan; Pan, Xin-Liang; Ding, Li-Jie; Liu, Da-Yu; Da-Peng Lei; Jin, Tong

2013-01-01

147

Altered Gene Expressions and Cytogenetic Repair Efficiency in Cells with Suppressed Expression of XPA after Proton Exposure  

NASA Technical Reports Server (NTRS)

Cellular responses to damages from ionizing radiation (IR) exposure are influenced not only by the genes involved in DNA double strand break (DSB) repair, but also by non- DSB repair genes. We demonstrated previously that suppressed expression of several non-DSB repair genes, such as XPA, elevated IR-induced cytogenetic damages. In the present study, we exposed human fibroblasts that were treated with control or XPA targeting siRNA to 250 MeV protons (0 to 4 Gy), and analyzed chromosome aberrations and expressions of genes involved in DNA repair. As expected, after proton irradiation, cells with suppressed expression of XPA showed a significantly elevated frequency of chromosome aberrations compared with control siRNA treated (CS) cells. Protons caused more severe DNA damages in XPA knock-down cells, as 36% cells contained multiple aberrations compared to 25% in CS cells after 4Gy proton irradiation. Comparison of gene expressions using the real-time PCR array technique revealed that expressions of p53 and its regulated genes in irradiated XPA suppressed cells were altered similarly as in CS cells, suggesting that the impairment of IR induced DNA repair in XPA suppressed cells is p53-independent. Except for XPA, which was more than 2 fold down regulated in XPA suppressed cells, several other DNA damage sensing and repair genes (GTSE1, RBBP8, RAD51, UNG and XRCC2) were shown a more than 1.5 fold difference between XPA knock-down cells and CS cells after proton exposure. The possible involvement of these genes in the impairment of DNA repair in XPA suppressed cells will be further investigated.

Zhang, Ye; Rohde, Larry H.; Gridley, Daila S.; Mehta, Satish K.; Pierson, Duane L.; Wu, Honglu

2009-01-01

148

Differential expression of microRNAs in mouse liver under aberrant energy metabolic status[S  

PubMed Central

Despite years of effort, exact pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains obscure. To gain an insight into the regulatory roles of microRNAs (miRNAs) in aberrant energy metabolic status and pathogenesis of NAFLD, we analyzed the expression of miRNAs in livers of ob/ob mice, streptozotocin (STZ)-induced type 1 diabetic mice, and normal C57BL/6 mice by miRNA microarray. Compared with normal C57BL/6 mice, ob/ob mice showed upregulation of eight miRNAs and downregulation of four miRNAs in fatty livers. Upregulation of miR-34a and downregulation of miR-122 was found in livers of STZ-induced diabetic mice. These results demonstrate that distinct miRNAs are strongly dysregulated in NAFLD and hyperglycemia. Comparison between miRNA expressions in livers of ob/ob mice and STZ-administered mice further revealed upregulation of four miRNAs and downregulation of two miRNAs in livers of ob/ob mice, indicating that these miRNAs may represent a molecular signature of NAFLD. A distinctive miRNA expression pattern was identified in ob/ob mouse liver, and hierarchical clustering of this pattern could clearly discriminate ob/ob mice from either normal C57BL/6 mice or STZ-administered mice. These findings suggest an important role of miRNAs in hepatic energy metabolism and implicate the participation of miRNAs in the pathophysiological processes of NAFLD. PMID:19372595

Li, Shengjie; Chen, Xi; Zhang, Hongjie; Liang, Xiangying; Xiang, Yang; Yu, Chaohui; Zen, Ke; Li, Youming; Zhang, Chen-Yu

2009-01-01

149

Differential gene expression profile of retinoblastoma compared to normal retina  

PubMed Central

Purpose The retinoblastoma gene (RB1) is a tumor suppressor gene that was first discovered in a rare ocular pediatric tumor called retinoblastoma (RB). The RB1 gene is essential for normal progression through the cell cycle and exerts part of its function through the family of transcription factors (E2F) and many other intermediaries. In the absence of normal RB1, genomic instability and chromosomal aberrations accumulate, leading to tumor initiation, progression, and ultimately metastasis. The purpose of this report was to identify the molecular pathways that are deregulated in retinoblastoma. Methods We compared gene expression signatures of matched normal retinal tissue and retinoblastoma (RB) tumor tissue from six individuals, using microarray analysis followed by statistical and bioinformatic analyses. Results We identified 1,116 genes with increased expression and 837 with decreased expression in RB tumor tissue compared to matched normal retinal tissue. Functional categories of the cognate genes with the greatest statistical support were cell cycle (309 genes), cell death (437 genes), DNA replication, recombination and repair (270 genes), cellular growth and proliferation (464 genes), and cellular assembly and organization (110 genes). The list included differentially expressed retinal cone-cell-specific markers. These data indicated the predominance of cone cells in RB and support the idea that the latter group of cells may be the cells of origin for RB. Conclusions The genes differentially expressed in RB as compared to normal retina belong mainly to DNA damage-response pathways, including, but not limited to, breast cancer associated genes (BRCA1, BRCA2), ataxia telangiectasia mutated gene (ATM), ataxia telangiectasia and Rad3 related gene(ATR), E2F, checkpoint kinase 1 (CHK1) genes. In addition, novel pathways, such as aryl hydrocarbon receptor (AHR) signaling, polo-like kinase and mitosis, purine metabolism pathways were involved. The molecules AHR, CHK1, and polo-like kinases are of particular interest because there are several currently available drugs that target these molecules. Further studies are needed to determine if targeting these pathways in RB will have therapeutic value. It is also important to evaluate the relative importance of these pathways in different cells that make up the normal retina. PMID:20664703

Shields, Carol L.

2010-01-01

150

Altered Expression of MGMT in High-Grade Gliomas Results from the Combined Effect of Epigenetic and Genetic Aberrations  

PubMed Central

MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy. PMID:23505468

Ramalho-Carvalho, Joăo; Pires, Malini; Lisboa, Susana; Graça, Inęs; Rocha, Patrícia; Barros-Silva, Joăo Diogo; Savva-Bordalo, Joana; Maurício, Joaquina; Resende, Mário; Teixeira, Manuel R.; Honavar, Mrinalini; Henrique, Rui; Jerónimo, Carmen

2013-01-01

151

Significance of Aberrant Expression of MicroRNAs in Cancer Cells  

Microsoft Academic Search

\\u000a Alterations in miRNA genes and other non-coding RNAs play a critical role in the pathophysiology of all human cancers: cancer\\u000a initiation and progression can involve microRNAs (miRNAs) – small non-coding RNAs that can regulate gene expression. At present,\\u000a the main mechanism of microRNoma (defined as the full complement of microRNAs present in a genome) alteration in cancer cells\\u000a seems to

George A. Calin; Chang-gong Liu; Manuela Ferracin; Stefano Volinia; Massimo Negrini; Carlo M. Croce

152

Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer  

PubMed Central

Secreted protein acidic and rich in cysteine (SPARC) gene has been shown to be epigenetically silenced in several cancers. We investigated the loss of expression and promoter methylation of this tumor suppressor gene in gastric cancers and correlated the data with clinicopathological features. We observed the loss of SPARC mRNA and SPARC protein expression in 7 of 10 (70%) gastric cancer cell lines. Upon treatment of expression-negative cell lines with a demethylating agent, expression of mRNA and protein was restored in all cells. Methylation rate of SPARC gene was 80% in ten gastric cancer cell lines and 74% (163 of 220) in primary tumors, while it was 5% in normal gastric mucosa (n = 40). In intestinal gastric cancer, SPARC methylation correlated with a negative prognosis (P < 0.001; relative risk 2.754, 95% confidence interval 1.780–4.261). Immunostaining revealed that SPARC protein was overexpressed in stromal fibroblasts adjacent to neoplastic epithelium but rarely expressed in the primary gastric cancer cells. These results implicate SPARC promoter methylation as an important factor in the tumorigenesis of gastric carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and the potential clinical importance in human gastric cancers. PMID:25516351

Chen, Zi-Yi; Zhang, Jun-Ling; Yao, Hong-Xin; Wang, Peng-Yuan; Zhu, Jing; Wang, Wei; Wang, Xin; Wan, Yuan-Lian; Chen, Shan-Wen; Chen, Guo-Wei; Liu, Yu-Cun

2014-01-01

153

Identifying The Most Significant Genes From Gene Expression Profiles For Sample Classification  

E-print Network

Identifying The Most Significant Genes From Gene Expression Profiles For Sample Classification of gene expression profiles. This generated gene data include complex variations of expression levels with the existing techniques. Keywords: Bioinformatics, Gene Selection, Gene Classification. I. INTRODUCTION The DNA

Al-Mubaid, Hisham

154

Sparse Statistical Modelling in Gene Expression Genomics  

E-print Network

context and illustration. The first data set arises from a gene expression experiment designed1 Sparse Statistical Modelling in Gene Expression Genomics Joe Lucasa , Carlos Carvalhoa , Quanli central to practical data anal- ysis and inference with increasingly high-dimensional data. Gene ex

West, Mike

155

Gene Expression Clustering with Functional Mixture Models  

E-print Network

Gene Expression Clustering with Functional Mixture Models Darya Chudova, Department of Computer measured on a discrete time grid. The model is specifically tailored to gene expression time course data of the model, and apply the proposed approach to the set of cycling genes in yeast. The experiments show

Mjolsness, Eric

156

Gene Expression Profiling in Developing Human Hippocampus  

E-print Network

Gene Expression Profiling in Developing Human Hippocampus Yan Zhang,1,2 Pinchao Mei,1­3 Rong Lou,1 Molecular Biology, Beijing, China 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York The gene into the developmental and functional character- istics, we analyzed the expression profile of active genes in developing

157

Gene Expression Omnibus: NCBI gene expression and hybridization array data repository  

Microsoft Academic Search

The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expres- sion databases

Ron Edgar; Michael Domrachev; Alex E. Lash

2002-01-01

158

Gene expression pattern Embryonic expression of a P2X3 receptor encoding gene in zebrash  

E-print Network

Gene expression pattern Embryonic expression of a P2X3 receptor encoding gene in zebra®sh William H genes during early development. Here we describe the expression of a gene (p2x3) encoding a P2X3., 1998; Xiang et al., 1998) that include the nociceptive neurones of the trigem- inal and dorsal root

Burnstock, Geoffrey

159

Gene Expression: Sizing it all up  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genomic architecture appears to be a largely unexplored component of gene expression. Although surely not the end of the story, we are learning that when it comes to gene expression, size is important. We have been surprised to find that certain patterns of expression, tissue-specific versus constit...

160

Aberrant CCR4 Expression Is Involved in Tumor Invasion of Lymph Node-Negative Human Gastric Cancer  

PubMed Central

Cellular chemotaxis is the best-known function of chemokine receptors which are closely linked with tumor metastasis. In fact, positive expression of chemokine receptors could also be identified even in some patients without metastatic tumors, while the clinical relevance of this data has not been fully established. Our studies were designed to clarify the CCR4 expression profiles and to explore its potential role in histologically node-negative (pN0) gastric cancer (GC). Immunohistochemistry (IHC) or immunohistofluorescence (IHF) analysis was performed on specimens obtained from 108 patients with pN0 GC. We found that CCR4 was aberrantly over-expressed inpN0 GC tissues, with different expression patterns on tumor cells and being associated with T-stage (P = 0.002). The matrigel in vitro invasion assay revealed that over-expression of CCR4 in GC cell lines significantly enhanced the invasive capacity of these cells. Results from real-time RT-PCR and gelatinzymography showed a significant increase in matrix metalloproteinase (MMP)-9 production induced by the forced expression of CCR4 in GC cell lines. Our data suggest that the aberrant CCR4 expression is involved in tumor invasion of pN0 GC and, conceivably, antagonists of CCR4 might be useful candidates for controlling early events in tumor progression. PMID:25790118

Yang, Xiaoyun; Qu, Ailin; Zhang, Xin; Zhou, Chengjun; Wang, Chuanxin

2015-01-01

161

Novel aberrant splicings caused by a splice site mutation (IVS1a+5g>a) in F7 gene.  

PubMed

Low FVII coagulant activity (FVII:C 8.2%) and antigen level (FVII:Ag 34.1%) in a 46-year-old Chinese male led to a diagnosis of coagulation factor VII (FVII) deficiency. Compound heterozygous mutations were identified in his F 7 gene:a G to A transition in the 5' donor splice site of intron 1a (IVS1a+5g>a) and a T to G transition at the nucleotide position 10961 in exon 8, resulting in a His to Gln substitution at amino acid residue 348. An analysis of ectopic transcripts of F7 in the leukocytes of the patient reveals that the mutation (IVS1a+5g>a) is associated with two novel aberrant patterns of splicing. The predominant alternative transcript removes exon 2, but retains intron 3, which shifts the reading frame and predicts a premature translation termination at the nucleotide positions 2-4 in intron 3. The minor alternative transcript skips both exon 2 and exon 3 (FVII Delta 2, 3), leading to an in-frame deletion of the propeptide and gamma-carboxylated glutamic acid (Gla) domains of mature FVII protein. In vitro expression studies of the alternative transcript FVII Delta 2,3 by transient transfection of HEK 293 cells with PcDNA 3.1(-) expression vector showed that although the mutant protein could be secreted, no pro-coagulation activity was detected. The coexistence of the two abnormal transcripts and a heterozygous mutation His348Gln, explained the patient's phenotype. PMID:15968391

Ding, Qiulan; Wu, Wenman; Fu, Qihua; Wang, Xuefeng; Hu, Yiqun; Wang, Hongli; Wang, Zhenyi

2005-06-01

162

Familial aggregation analysis of gene expressions  

PubMed Central

Traditional studies of familial aggregation are aimed at defining the genetic (and non-genetic) causes of a disease from physiological or clinical traits. However, there has been little attempt to use genome-wide gene expressions, the direct phenotypic measures of genes, as the traits to investigate several extended issues regarding the distributions of familially aggregated genes on chromosomes or in functions. In this study we conducted a genome-wide familial aggregation analysis by using the in vitro cell gene expressions of 3300 human autosome genes (Problem 1 data provided to Genetic Analysis Workshop 15) in order to answer three basic genetics questions. First, we investigated how gene expressions aggregate among different types (degrees) of relative pairs. Second, we conducted a bioinformatics analysis of highly familially aggregated genes to see how they are distributed on chromosomes. Third, we performed a gene ontology enrichment test of familially aggregated genes to find evidence to support their functional consensus. The results indicated that 1) gene expressions did aggregate in families, especially between sibs. Of 3300 human genes analyzed, there were a total of 1105 genes with one or more significant (empirical p < 0.05) familial correlation; 2) there were several genomic hot spots where highly familially aggregated genes (e.g., the chromosome 6 HLA genes cluster) were clustered; 3) as we expected, gene ontology enrichment tests revealed that the 1105 genes were aggregating not only in families but also in functional categories. PMID:18466548

Rao, Shao-Qi; Xu, Liang-De; Zhang, Guang-Mei; Li, Xia; Li, Lin; Shen, Gong-Qing; Jiang, Yang; Yang, Yue-Ying; Gong, Bin-Sheng; Jiang, Wei; Zhang, Fan; Xiao, Yun; Wang, Qing K

2007-01-01

163

Methods for monitoring multiple gene expression  

SciTech Connect

The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

Berka, Randy (Davis, CA); Bachkirova, Elena (Davis, CA); Rey, Michael (Davis, CA)

2008-06-01

164

Methods for monitoring multiple gene expression  

DOEpatents

The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

Berka, Randy; Bachkirova, Elena; Rey, Michael

2013-10-01

165

Methods for monitoring multiple gene expression  

DOEpatents

The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

Berka, Randy (Davis, CA); Bachkirova, Elena (Davis, CA); Rey, Michael (Davis, CA)

2012-05-01

166

Microarray Gene Expression Data Society  

NSDL National Science Digital Library

The Microarray Gene Expression Data Society is an international organization composed of computer scientists, data analysts, and biologists "that aims to facilitate the sharing of microarray data generated by functional genomics and proteomics experiments." Hosted by the European Bioinformatics Institute, this website connects to information about six major Data Society workgroups (e.g. the Ontology Working Group, the Reporting Structure for Biological Investigations Working Groups, the Data Transformation and Normalization Working Group). The Data Society website also offers a News Archive; several downloadable publications from the past few years; a number of PowerPoint presentations from past Society meetings; contact information for Society Board Members; and links to information about upcoming and past Society meetings.

167

MUC7 gene expression and genetic polymorphism  

Microsoft Academic Search

This study examined differential expression of several mucin genes in the human submandibular gland and trachea, MUC7 tissue\\u000a and species specificity, and MUC7 genetic polymorphism. Mucin gene expression examined by RT-PCR indicated that MUC1, MUC4\\u000a and MUC7 are expressed in the human submandibular gland, while MUC1, MUC2, MUC4, MUC5 and MUC7 are expressed in the human\\u000a trachea. Northern blot analysis

Aaron R. Biesbrock; Libuse A. Bobek; Michael J. Levine

1997-01-01

168

Gene expression. MicroRNA control of protein expression noise.  

PubMed

MicroRNAs (miRNAs) repress the expression of many genes in metazoans by accelerating messenger RNA degradation and inhibiting translation, thereby reducing the level of protein. However, miRNAs only slightly reduce the mean expression of most targeted proteins, leading to speculation about their role in the variability, or noise, of protein expression. We used mathematical modeling and single-cell reporter assays to show that miRNAs, in conjunction with increased transcription, decrease protein expression noise for lowly expressed genes but increase noise for highly expressed genes. Genes that are regulated by multiple miRNAs show more-pronounced noise reduction. We estimate that hundreds of (lowly expressed) genes in mouse embryonic stem cells have reduced noise due to substantial miRNA regulation. Our findings suggest that miRNAs confer precision to protein expression and thus offer plausible explanations for the commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes. PMID:25838385

Schmiedel, Jörn M; Klemm, Sandy L; Zheng, Yannan; Sahay, Apratim; Blüthgen, Nils; Marks, Debora S; van Oudenaarden, Alexander

2015-04-01

169

Hematopoietic expression of oncogenic BRAF promotes aberrant growth of monocyte-lineage cells resistant to PLX4720  

PubMed Central

Mutational activation of BRAF leading to expression of the BRAFV600E oncoprotein was recently identified in a high percentage of specific hematopoietic neoplasms in monocyte/histiocyte and mature B-cell lineages. Although BRAFV600E is a driver oncoprotein and pharmacological target in solid tumors such as melanoma, lung and thyroid cancer, it remains unknown whether BRAFV600E is an appropriate therapeutic target in hematopoietic neoplasms. To address this critical question, we generated a mouse model expressing inducible BRAFV600E in the hematopoietic system, and evaluated the efficacy of pathway-targeted therapeutics against primary hematopoietic cells. In this model, BRAFV600E expression conferred cytokine-independent growth to monocyte/macrophage-lineage progenitors leading to aberrant in vivo and in vitro monocyte/macrophage expansion. Furthermore, transplantation of BRAFV600E-expressing bone marrow cells promoted an in vivo pathology most notable for monocytosis in hematopoietic tissues and visceral organs. In vitro analysis revealed that MEK inhibition, but not RAF inhibition, effectively suppressed cytokine-independent clonal growth of monocyte/macrophage-lineage progenitors. However, combined RAF and PI3K inhibition effectively inhibited cytokine-independent colony formation, suggesting autocrine PI3K pathway activation. Taken together, these results provide evidence that constitutively activated BRAFV600E drives aberrant proliferation of monocyte-lineage cells. This study supports the development of pathway-targeted therapeutics in the treatment of BRAFV600E-expressing hematopoietic neoplasms in the monocyte/histiocyte lineage. PMID:24152792

Kamata, Tamihiro; Dankort, David; Kang, Jing; Giblett, Susan; Pritchard, Catrin A.; McMahon, Martin; Leavitt, Andrew D.

2013-01-01

170

Expression Profile of the REG Gene Family in Colorectal Carcinoma  

PubMed Central

Regenerating (REG) gene family belongs to the calcium-dependent lectin gene superfamily and encodes small multifunctional secretory proteins, which might be involved in cell proliferation, differentiation, and carcinogenesis. To clarify REG expression profile in colorectal carcinoma (CRC), the authors examined the expression of REG I?, I?, III, HIP/PAP, and REG IV by immunohistochemistry on tissue microarray. The expression of REG I?, III, and HIP/PAP was more frequently observed in the CRCs than adjacent non-neoplastic mucosa (p < 0.001), whereas it was the converse for REG I? and IV (p < 0.001). The expression of REG I?, I?, III, and HIP/PAP was negatively correlated with the depth of invasion of CRCs (p < 0.05). The REG I? and HIP/PAP were less expressed in CRCs with than without venous invasion (p < 0.05). The positive rates of REG I? and HIP/PAP were significantly higher in CRCs without than with lymph node metastasis (p < 0.05). Mucinous carcinoma more frequently expressed REG IV protein than well- and moderately differentiated ones (p < 0.05). There was a positive relationship between REG I?, I?, III, and HIP/PAP expression (p < 0.05). Survival analysis indicated the REG I? or HIP/PAP expression was positively linked to favorable prognosis of carcinoma patients (p < 0.05). This study indicated that aberrant REG expression might be closely linked to the pathogenesis, invasion, or lymph node metastasis of CRCs. REG I? and HIP/PAP could be considered reliable markers of favorable prognosis of CRC patients. PMID:21339177

Zheng, Hua-chuan; Sugawara, Akira; Okamoto, Hiroshi; Takasawa, Shin; Takahashi, Hiroyuki; Masuda, Shinji; Takano, Yasuo

2011-01-01

171

Chapter 6: The Gene Expression Omnibus (GEO): A Gene Expression and Hybridization Repository  

E-print Network

Chapter 6: The Gene Expression Omnibus (GEO): A Gene Expression and Hybridization Repository Ron Edgar Alex Lash Summary The Gene Expression Omnibus (GEO) project was initiated at NCBI in 1999 experiments. GEO has a flexible and open design that allows the submission, storage, and retrieval of many

Levin, Judith G.

172

Gene expression pattern Nested expression and sequential downregulation of the Xenopus caudal genes  

E-print Network

Gene expression pattern Nested expression and sequential downregulation of the Xenopus caudal genes genes initiates during early gastrulation exhibiting a dorsoventral asymmetry in their domains of transcription. At mid-gastrulation the ventral preference becomes stronger and the caudal genes take up

Blumberg, Bruce

173

Gene expression profiles in skeletal muscle after gene electrotransfer  

Microsoft Academic Search

BACKGROUND: Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by

Pernille Hojman; John R Zibert; Hanne Gissel; Jens Eriksen; Julie Gehl

2007-01-01

174

Discriminatory Mining of Gene Expression Microarray Data  

Microsoft Academic Search

Recent advances in machine learning and pattern recognition methods provide new analytical tools to explore high dimensional gene expression microarray data. Our data mining software, VISual Data Analyzer for cluster discovery (VISDA), reveals many distinguishing patterns among gene expression profiles, which are responsible for the cell's phenotypes. The model-supported exploration of high-dimensional data space is achieved through two complementary schemes:

Zuyi Wang; Yue Wang; Jianping Lu; Sun-yuan Kung; Junying Zhang; Richard Lee; Jianhua Xuan; Javed I. Khan; Robert Clarke

2003-01-01

175

Idiomatic (gene) expressions Matthew V. Rockman  

E-print Network

of these dif- ferences that make a difference are non-coding cis- regulatory variants, which, unlike coding- regulatory variants that influence gene expression--its induc- tion, level, developmental timing and spatialIdiomatic (gene) expressions Matthew V. Rockman Summary Hidden among the myriad nucleotide variants

Rockman, Matthew

176

Designing Neural Networks Using Gene Expression Programming  

E-print Network

1 Designing Neural Networks Using Gene Expression Programming CândidaFerreira Gepsoft, 73 Elmtree. In this work it is shown how the chromosomes of Gene Expression Programming can be modified so that a complete is a computational device that consists of many simple connected units (neurons) that work in parallel

Fernandez, Thomas

177

NEUROSYSTEMS Gene expression analysis in the parvalbumin-  

E-print Network

typical markers of long-axon, projecting neurons (e.g. VGlut2), but also co-expressing genes typicalNEUROSYSTEMS Gene expression analysis in the parvalbumin- immunoreactive PV1 nucleus of the mouse-immunoreactive neurons has been previously observed in the rodent ventrolateral hypothalamus. However, the function

Eddy, Sean

178

Gene Expression Profiling in the Aging Ovary  

PubMed Central

DNA microarray is an important discovery technology that allows the analysis of the expression of thousands of genes at a time. Data from DNA microarrays elucidate fundamental biological processes through discovery of differential expression of genes not previously known or predicted to be involved in a particular process. In the ovary and other hormone-responsive tissues, the technology can be used to examine the effects of gene mutations, pharmaceutical agents, disease, hormones, developmental changes, or changes in gene expression related to aging. PMID:19763498

Eyster, Kathleen M.; Brannian, John D.

2015-01-01

179

Excision of uracil from transcribed DNA negatively affects gene expression.  

PubMed

Uracil is an unavoidable aberrant base in DNA, the repair of which takes place by a highly efficient base excision repair mechanism. The removal of uracil from the genome requires a succession of intermediate products, including an abasic site and a single strand break, before the original DNA structure can be reconstituted. These repair intermediates are harmful for DNA replication and also interfere with transcription under cell-free conditions. However, their relevance for cellular transcription has not been proved. Here we investigated the influence of uracil incorporated into a reporter vector on gene expression in human cells. The expression constructs contained a single uracil opposite an adenine (to mimic dUTP misincorporation during DNA synthesis) or a guanine (imitating a product of spontaneous cytosine deamination). We found no evidence for a direct transcription arrest by uracil in either of the two settings because the vectors containing the base modification exhibited unaltered levels of enhanced GFP reporter gene expression at early times after delivery to cells. However, the gene expression showed a progressive decline during subsequent hours. In the case of U:A pairs, this effect was retarded significantly by knockdown of UNG1/2 but not by knockdown of SMUG1 or thymine-DNA glycosylase uracil-DNA glycosylases, proving that it is base excision by UNG1/2 that perturbs transcription of the affected gene. By contrast, the decline of expression of the U:G constructs was not influenced by either UNG1/2, SMUG1, or thymine-DNA glycosylase knockdown, strongly suggesting that there are substantial mechanistic or kinetic differences between the processing of U:A and U:G lesions in cells. PMID:24951587

Lühnsdorf, Bork; Epe, Bernd; Khobta, Andriy

2014-08-01

180

The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3  

PubMed Central

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications. PMID:23637629

Kooistra, Susanne M.; Malatesta, Martina; Morales Torres, Cristina; Rekling, Jens C.; Johansen, Jens V.; Abarrategui, Iratxe; Helin, Kristian

2013-01-01

181

Quality Measures for Gene Expression Biclusters  

PubMed Central

An noticeable number of biclustering approaches have been proposed proposed for the study of gene expression data, especially for discovering functionally related gene sets under different subsets of experimental conditions. In this context, recognizing groups of co-expressed or co-regulated genes, that is, genes which follow a similar expression pattern, is one of the main objectives. Due to the problem complexity, heuristic searches are usually used instead of exhaustive algorithms. Furthermore, most of biclustering approaches use a measure or cost function that determines the quality of biclusters. Having a suitable quality metric for bicluster is a critical aspect, not only for guiding the search, but also for establishing a comparison criteria among the results obtained by different biclustering techniques. In this paper, we analyse a large number of existing approaches to quality measures for gene expression biclusters, as well as we present a comparative study of them based on their capability to recognize different expression patterns in biclusters. PMID:25763839

Pontes, Beatriz; Girldez, Ral; Aguilar-Ruiz, Jess S.

2015-01-01

182

Clustering Genes Using Gene Expression and Text Literature Data  

Microsoft Academic Search

Clustering of gene expression data is a stan- dard technique used to identify closely related genes. In this paper, we develop a new clustering algorithm, MSC (Multi-Source Clustering), to perform exploratory analysis using two or more diverse sources of data. In particular, we investi- gate the problem of improving the clustering by integrating information obtained from gene ex- pression data

Chengyong Yang; Erliang Zeng; Tao Li; Giri Narasimhan

2005-01-01

183

Sparse Statistical Modelling in Gene Expression Genomics  

E-print Network

rich data sets are used to provide context and illustration. The first data set arises from a gene1 Sparse Statistical Modelling in Gene Expression Genomics Joe Lucasa , Carlos Carvalhoa , Quanli Wanga,b , Andrea Bildb , Joe Nevinsb and Mike Westa Duke University In: Bayesian Inference for Gene

West, Mike

184

Gene Expression Profiling during Murine Tooth Development  

PubMed Central

The aim of this study was to describe the expression of genes, including ameloblastin (Ambn), amelogenin X chromosome (Amelx), and enamelin (Enam) during early (pre-secretory) tooth development. The expression of these genes has predominantly been studied at post-secretory stages. Deoxyoligonucleotide microarrays were used to study gene expression during development of the murine first molar tooth germ at 24?h intervals, starting at the 11th embryonic day (E11.5), and up to the 7th day after birth (P7). The profile search function of Spotfire software was used to select genes with similar expression profile as the enamel genes (Ambn, Amelx, and Enam). Microarray results where validated using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), and translated proteins identified by Western-blotting. In situ localization of the Ambn, Amelx, and Enam mRNAs were monitored from E12.5 to E17.5 using deoxyoligonucleotide probes. Bioinformatics analysis was used to associate biological functions with differentially expressed (DE; p???0.05) genes. Microarray results showed a total of 4362 genes including Ambn, Amelx, and Enam to be significant DE throughout the time-course. The expression of the three enamel genes was low at pre-natal stages (E11.5–P0) increasing after birth (P1–P7). Profile search lead to isolation of 87 genes with significantly similar expression to the three enamel proteins. These mRNAs were expressed in dental epithelium and epithelium derived cells. Although expression of Ambn, Amelx, and Enam were lower during early tooth development compared to secretory stages enamel proteins were detectable by Western-blotting. Bioinformatic analysis associated the 87 genes with multiple biological functions. Around 35 genes were associated with 15 transcription factors. PMID:22866057

Landin, Maria A. dos Santos Silva; Shabestari, Maziar; Babaie, Eshrat; Reseland, Janne E.; Osmundsen, Harald

2012-01-01

185

Regulation of KSHV Lytic Gene Expression  

Microsoft Academic Search

The life cycle of KSHV, latency versus lytic replication, is mainly determined at the transcriptional regulation level. A\\u000a viral immediate-early gene product, replication and transcription activator (RTA), has been identified as the molecular switch\\u000a for initiation of the lytic gene expression program from latency. Here we review progress on two key questions: how RTA gene\\u000a expression is controlled by viral

H. Deng; Y. Liang; R. Sun

186

Gene expression trees in lymphoid development  

PubMed Central

Background The regulatory processes that govern cell proliferation and differentiation are central to developmental biology. Particularly well studied in this respect is the lymphoid system due to its importance for basic biology and for clinical applications. Gene expression measured in lymphoid cells in several distinguishable developmental stages helps in the elucidation of underlying molecular processes, which change gradually over time and lock cells in either the B cell, T cell or Natural Killer cell lineages. Large-scale analysis of these gene expression trees requires computational support for tasks ranging from visualization, querying, and finding clusters of similar genes, to answering detailed questions about the functional roles of individual genes. Results We present the first statistical framework designed to analyze gene expression data as it is collected in the course of lymphoid development through clusters of co-expressed genes and additional heterogeneous data. We introduce dependence trees for continuous variates, which model the inherent dependencies during the differentiation process naturally as gene expression trees. Several trees are combined in a mixture model to allow inference of potentially overlapping clusters of co-expressed genes. Additionally, we predict microRNA targets. Conclusion Computational results for several data sets from the lymphoid system demonstrate the relevance of our framework. We recover well-known biological facts and identify promising novel regulatory elements of genes and their functional assignments. The implementation of our method (licensed under the GPL) is available at . PMID:17925013

Costa, Ivan G; Roepcke, Stefan; Schliep, Alexander

2007-01-01

187

Regulation Of Mammalian Myb Gene Expression  

Microsoft Academic Search

Although the precise molecular mechanisms that govern mammalian myb (cmyb, B-myb (MybL2) and A-myb (MybL1)) gene expression are yet to be resolved, a collective understanding is beginning to emerge. At present, it is evident that\\u000a distinct regulatory factors and mechanisms control expression of the mammalian myb genes, and this is presumably reflected in the defined expression patterns of individual family

Fiona J. Tavner

188

Methodological Limitations in Determining Astrocytic Gene Expression  

PubMed Central

Traditionally, astrocytic mRNA and protein expression are studied by in situ hybridization (ISH) and immunohistochemically. This led to the concept that astrocytes lack aralar, a component of the malate-aspartate-shuttle. At least similar aralar mRNA and protein expression in astrocytes and neurons isolated by fluorescence-assisted cell sorting (FACS) reversed this opinion. Demonstration of expression of other astrocytic genes may also be erroneous. Literature data based on morphological methods were therefore compared with mRNA expression in cells obtained by recently developed methods for determination of cell-specific gene expression. All Na,K-ATPase-? subunits were demonstrated by immunohistochemistry (IHC), but there are problems with the cotransporter NKCC1. Glutamate and GABA transporter gene expression was well determined immunohistochemically. The same applies to expression of many genes of glucose metabolism, whereas a single study based on findings in bacterial artificial chromosome (BAC) transgenic animals showed very low astrocytic expression of hexokinase. Gene expression of the equilibrative nucleoside transporters ENT1 and ENT2 was recognized by ISH, but ENT3 was not. The same applies to the concentrative transporters CNT2 and CNT3. All were clearly expressed in FACS-isolated cells, followed by biochemical analysis. ENT3 was enriched in astrocytes. Expression of many nucleoside transporter genes were shown by microarray analysis, whereas other important genes were not. Results in cultured astrocytes resembled those obtained by FACS. These findings call for reappraisal of cellular nucleoside transporter expression. FACS cell yield is small. Further development of cell separation methods to render methods more easily available and less animal and cost consuming and parallel studies of astrocytic mRNA and protein expression by ISH/IHC and other methods are necessary, but new methods also need to be thoroughly checked. PMID:24324456

Peng, Liang; Guo, Chuang; Wang, Tao; Li, Baoman; Gu, Li; Wang, Zhanyou

2013-01-01

189

Differential expression of chlamydial signal transduction genes in normal and interferon gamma-induced persistent Chlamydophila pneumoniae infections  

Microsoft Academic Search

Characteristic features of the persistent chlamydial developmental cycle, associated with chronic infections in both humans and animals, include the generation of non-replicative, morphologically aberrant bodies which are distinct from normal propagating reticulate bodies. Previous studies have correlated these morphological and metabolic changes with differential expression of diverse functional subsets of chlamydial genes. To further investigate these correlations, we compared mRNA

Adam Polkinghorne; Richard J. Hogan; Lloyd Vaughan; James T. Summersgill; Peter Timms

2006-01-01

190

Regulatory Protein Coordinating Gene Expression  

NSDL National Science Digital Library

The action of the glucocorticoid receptor is illustrated. On the left is shown a series of genes, each of which has various gene activator proteins bound to its regulatory region. However, these bound proteins are not sufficient on their own to activate transcription efficiently. On the right is shown the effects of adding an additional gene regulatory protein

BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts; Bruce REV:2005-04-16 END:VCARD

1998-07-01

191

Aberrant expression of long noncoding RNAs in chronic thromboembolic pulmonary hypertension  

PubMed Central

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the primary causes of severe pulmonary hypertension. In order to identify long noncoding RNAs (lncRNAs) that may be involved in the development of CTEPH, comprehensive lncRNA and messenger RNA (mRNA) profiling of endothelial tissues from the pulmonary arteries of CTEPH patients was conducted with microarray analysis. Differential expression of 185 lncRNAs was observed in the CTEPH tissues compared with healthy control tissues. Further analysis identified 464 regulated enhancer-like lncRNAs and overlapping, antisense or nearby mRNA pairs. Coexpression networks were subsequently constructed and investigated. The expression levels of the lncRNAs, NR_036693, NR_027783, NR_033766 and NR_001284, were significantly altered. Gene ontology and pathway analysis demonstrated the potential role of lncRNAs in the regulation of central process, including inflammatory response, response to endogenous stimulus and antigen processing and presentation. The use of bioinformatics may help to uncover and analyze large quantities of data identified by microarray analyses, through rigorous experimental planning, statistical analysis and the collection of more comprehensive data regarding CTEPH. The results of the present study provided evidence which may be helpful in future studies on the diagnosis and management of CTEPH. PMID:25522749

GU, SONG; LI, GUANGHUI; ZHANG, XITAO; YAN, JUN; GAO, JIE; AN, XIANGGUANG; LIU, YAN; SU, PIXIONG

2015-01-01

192

Aberrant expression of long noncoding RNAs in chronic thromboembolic pulmonary hypertension.  

PubMed

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the primary causes of severe pulmonary hypertension. In order to identify long noncoding RNAs (lncRNAs) that may be involved in the development of CTEPH, comprehensive lncRNA and messenger RNA (mRNA) profiling of endothelial tissues from the pulmonary arteries of CTEPH patients was conducted with microarray analysis. Differential expression of 185 lncRNAs was observed in the CTEPH tissues compared with healthy control tissues. Further analysis identified 464 regulated enhancer?like lncRNAs and overlapping, antisense or nearby mRNA pairs. Coexpression networks were subsequently constructed and investigated. The expression levels of the lncRNAs, NR_036693, NR_027783, NR_033766 and NR_001284, were significantly altered. Gene ontology and pathway analysis demonstrated the potential role of lncRNAs in the regulation of central process, including inflammatory response, response to endogenous stimulus and antigen processing and presentation. The use of bioinformatics may help to uncover and analyze large quantities of data identified by microarray analyses, through rigorous experimental planning, statistical analysis and the collection of more comprehensive data regarding CTEPH. The results of the present study provided evidence which may be helpful in future studies on the diagnosis and management of CTEPH. PMID:25522749

Gu, Song; Li, Guanghui; Zhang, Xitao; Yan, Jun; Gao, Jie; An, Xiangguang; Liu, Yan; Su, Pixiong

2015-04-01

193

Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells  

SciTech Connect

Germ cell mutagenicity testing provides experimental data to quantify genetic risk for exposed human populations. The majority of tests are performed with exposure of males, and female data are relatively rare. The reason for this paucity lies in the differences between male and female germ cell biology. Male germ cells are produced throughout reproductive life and all developmental stages can be ascertained by appropriate breeding schemes. In contrast, the female germ cell pool is limited, meiosis begins during embryogenesis and oocytes are arrested over long periods of time until maturation processes start for small numbers of oocytes during the oestrus cycle in mature females. The literature data are reviewed to point out possible gender differences of germ cells to exogenous agents such as chemicals or ionizing radiation. From the limited information, it can be concluded that male germ cells are more sensitive than female germ cells to the induction of chromosomal aberrations and gene mutations. However, exceptions are described which shed doubt on the extrapolation of experimental data from male rodents to the genetic risk of the human population. Furthermore, the female genome may be more sensitive to mutation induction during peri-conceptional stages compared to the male genome of the zygote. With few exceptions, germ cell experiments have been carried out under high acute exposure to optimize the effects and to compensate for the limited sample size in animal experiments. Human exposure to environmental agents, on the other hand, is usually chronic and involves low doses. Under these conditions, gender differences may become apparent that have not been studied so far. Additionally, data are reviewed that suggest a false impression of safety when responses are negative under high acute exposure of male rodents while a mutational response is induced by low chronic exposure. The classical (morphological) germ cell mutation tests are not performed anymore because they are animal and time consuming. Nevertheless, information is needed to place genetic risk extrapolations on more solid grounds and thereby to prevent an increased genetic burden to future generations. It is pointed out that modern molecular methodologies are available now to experimentally address the open questions.

Adler, Ilse-Dore [GSF-Institute of Experimental Genetics, Neuherberg D-85758 (Germany); Carere, Angelo [Istituto Superiore di Sanita, Viale Regina Elena 299, Rome 00161 (Italy); Eichenlaub-Ritter, Ursula [Institute of Genetechnology/Microbiology, University of Bielefeld, Bielefeld D-33501 (Germany)]. E-mail: EiRi@uni-bielefeld.de; Pacchierotti, Francesca [Section of Toxicology and Biomedical Sciences, ENEA, CR Casaccia, Via Anguillarese 301, Rome 00060 (Italy)

2007-05-15

194

Expression of the DISC1 Gene  

NSDL National Science Digital Library

Gene expression is the process of converting genetic information encoded in the brain into a final product (a protein or RNA). Uncovering where a given gene's protein is most commonly expressed in the body can yield vital clues as to the purpose of that gene. DISC1 expression has been traced to neurons in a number of areas in the brain, particularly the hippocampus. It is associated with synaptic function, suggesting that one of its adult functions may be synaptic plasticity, a process that underlines learning and memory.

2009-04-14

195

Gene expression in the Parkinson's disease brain  

PubMed Central

The study of gene expression has undergone a transformation in the past decade as the benefits of the sequencing of the human genome have made themselves felt. Increasingly, genome wide approaches are being applied to the analysis of gene expression in human disease as a route to understanding the underlying pathogenic mechanisms. In this review, we will summarise current state of gene expression studies of the brain in Parkinson's disease, and examine how these techniques can be used to gain an insight into aetiology of this devastating disorder. PMID:22173063

Lewis, Patrick A.; Cookson, Mark R.

2012-01-01

196

Aberrant splicing and transcription termination caused by P element insertion into the intron of a Drosophila gene  

SciTech Connect

Insertional mutagenesis screens using the P[lacZ, rosy{sup +}] (PZ) transposable element have provided thousands of mutant lines for analyzing genes of varied function in the fruitfly, Drosophila melanogaster. As has been observed with other P elements, many of the PZ-induced mutations result from insertion of the P element into the promoter or 5{prime} untranslated regions of the affected gene. We document here a novel mechanism for mutagenesis by this element. We show that sequences present within the element direct aberrant splicing and termination events that produce an mRNA composed of 5{prime} sequences from the mutated gene (in this case, pipsqueak) and 3{prime} sequences from within the P[lacZ, rosy{sup +}] element. These truncated RNAs could yield proteins with dominant mutant effects. 43 refs., 4 figs.

Horowitz, H.; Berg, C.A. [Univ. of Washington, Seattle, WA (United States)

1995-01-01

197

Individual Retinal Progenitor Cells Display Extensive Heterogeneity of Gene Expression  

E-print Network

Individual Retinal Progenitor Cells Display Extensive Heterogeneity of Gene Expression Jeffrey M processes undoubtedly depend at least in part upon variations among the gene expression programs among progenitor cells of a particular tissue. Here, we used comprehensive gene expression profiling

Tabin, Cliff

198

Differential Gene Expression in Ovarian Carcinoma  

PubMed Central

Ovarian cancer remains the fifth leading cause of cancer death for women in the United States. In this study, the gene expression of 20 ovarian carcinomas, 17 ovarian carcinomas metastatic to the omentum, and 50 normal ovaries was determined by Gene Logic Inc. using Affymetrix GeneChip HU_95 arrays containing ?12,000 known genes. Differences in gene expression were quantified as fold changes in gene expression in ovarian carcinomas compared to normal ovaries and ovarian carcinoma metastases. Genes up-regulated in ovarian carcinoma tissue samples compared to more than 300 other normal and diseased tissue samples were identified. Seven genes were selected for further screening by immunohistochemistry to determine the presence and localization of the proteins. These seven genes were: the ?8 integrin subunit, bone morphogenetic protein-7, claudin-4, collagen type IX ?2, cellular retinoic acid binding protein-1, forkhead box J1, and S100 calcium-binding protein A1. Statistical analyses showed that the ?8 integrin subunit, claudin-4, and S100A1 provided the best distinction between ovarian carcinoma and normal ovary tissues, and may serve as the best candidate tumor markers among the seven genes studied. These results suggest that further exploration into other up-regulated genes may identify novel diagnostic, therapeutic, and/or prognostic biomarkers in ovarian carcinoma. PMID:15277215

Hibbs, Kathleen; Skubitz, Keith M.; Pambuccian, Stefan E.; Casey, Rachael C.; Burleson, Kathryn M.; Oegema, Theodore R.; Thiele, Jeannine J.; Grindle, Suzanne M.; Bliss, Robin L.; Skubitz, Amy P.N.

2004-01-01

199

Aberrant DNA methylation and tumor suppressive activity of the EBF3 gene in gastric carcinoma.  

PubMed

The early B-cell factors (EBFs) are a group of four highly conserved DNA-binding transcription factors with an atypical zinc-finger and a helix-loop-helix domain. The EBF3 locus on chromosome 10q26.3 is epigenetically silenced or deleted in several types of cancers. In addition, EBF3 activates genes involved in cell cycle arrest and inhibits cell survival. However, inactivation of EBF3 gene expression was not fully studied in gastric carcinoma and the functions of EBF3 that underlie EBF3-regulated tumor suppression have not been identified. In our study, we found that inactivation of the EBF3 gene is frequently accompanied by promoter region hypermethylation in several gastric cancer cell lines and that the gene is reactivated by 5-aza-2'-deoxycytidine (5-aza-dc) and/or trichostatin A (TSA) in all ten gastric cancer cell lines. We performed functional analysis using small interfering RNA or expressional cDNA transfection in gastric cancer cell lines and demonstrate that EBF3 represses gastric cancer cell growth and migration, but activates cell cycle arrest and apoptosis. Promoter methylation of EBF3 was detected in 42/104 (40.4%) gastric cancer tissues but not in normal gastric tissues. Furthermore, promoter methylation of EBF3 was found to be significantly correlated with lymphatic invasion (p = 0.013) and poor survival (p = 0.038) in gastric carcinoma. These results suggest that EBF3 tumor suppressor is epigenetically silenced and that it serves as an independent prognostic marker in gastric carcinoma. PMID:21387304

Kim, Jin; Min, Sun Young; Lee, Hee Eun; Kim, Woo Ho

2012-02-15

200

Discovery of genes expressed in Hydra embryogenesis.  

PubMed

Hydra's remarkable capacity to regenerate, to proliferate asexually by budding, and to form a pattern de novo from aggregates allows studying complex cellular and molecular processes typical for embryonic development. The underlying assumption is that patterning in adult hydra tissue relies on factors and genes which are active also during early embryogenesis. Previously, we reported that in Hydra the timing of expression of conserved regulatory genes, known to be involved in adult patterning, differs greatly in adults and embryos (Fröbius, A.C., Genikhovich, G., Kürn, U., Anton-Erxleben, F. and Bosch, T.C.G., 2003. Expression of developmental genes during early embryogenesis of Hydra. Dev. Genes Evol. 213, 445-455). Here, we describe an unbiased screening strategy to identify genes that are relevant to Hydra vulgaris embryogenesis. The approach yielded two sets of differentially expressed genes: one set was expressed exclusively or nearly exclusively in the embryos, while the second set was upregulated in embryos in comparison to adult polyps. Many of the genes identified in hydra embryos had no matches in the database. Among the conserved genes upregulated in embryos is the Hydra orthologue of Embryonic Ectoderm Development (HyEED). The expression pattern of HyEED in developing embryos suggests that interstitial stem cells in Hydra originate in the endoderm. Importantly, the observations uncover previously unknown differences in genes expressed by embryos and polyps and indicate that not only the timing of expression of developmental genes but also the genetic context is different in Hydra embryos compared to adults. PMID:16337937

Genikhovich, Grigory; Kürn, Ulrich; Hemmrich, Georg; Bosch, Thomas C G

2006-01-15

201

Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers of  

E-print Network

Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma sera. Results: Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed

Hammerton, James

202

Sexual differences of imprinted genes' expression levels  

PubMed Central

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

Faisal, Mohammad; Kim, Hana; Kim, Joomyeong

2013-01-01

203

Feedback control of gene expression  

Microsoft Academic Search

Although feedback regulation of photosynthesis by carbon metabolites has long been recognized and investigated, its underlying molecular mechanisms remain unclear. The recent discovery that glucose and acetate trigger global repression of maize photosynthetic gene transcription provides the first direct evidence that a fundamental mechanism is used for feedback regulation of photosynthesis in higher plants. The metabolic repression of photosynthetic genes

Jen Sheen

1994-01-01

204

Regulation of meiotic gene expression in plants  

PubMed Central

With the recent advances in genomics and sequencing technologies, databases of transcriptomes representing many cellular processes have been assembled. Meiotic transcriptomes in plants have been studied in Arabidopsis thaliana, rice (Oryza sativa), wheat (Triticum aestivum), petunia (Petunia hybrida), sunflower (Helianthus annuus), and maize (Zea mays). Studies in all organisms, but particularly in plants, indicate that a very large number of genes are expressed during meiosis, though relatively few of them seem to be required for the completion of meiosis. In this review, we focus on gene expression at the RNA level and analyze the meiotic transcriptome datasets and explore expression patterns of known meiotic genes to elucidate how gene expression could be regulated during meiosis. We also discuss mechanisms, such as chromatin organization and non-coding RNAs that might be involved in the regulation of meiotic transcription patterns. PMID:25202317

Zhou, Adele; Pawlowski, Wojciech P.

2014-01-01

205

Dynamic modeling of gene expression data  

NASA Technical Reports Server (NTRS)

We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by singular value decomposition. The resulting time translation matrix provides a measure of the relationships among the modes and governs their time evolution. We show that a truncated matrix linking just a few modes is a good approximation of the full time translation matrix. This finding suggests that the number of essential connections among the genes is small.

Holter, N. S.; Maritan, A.; Cieplak, M.; Fedoroff, N. V.; Banavar, J. R.

2001-01-01

206

Population-level control of gene expression  

NASA Astrophysics Data System (ADS)

Gene expression is the process that translates genetic information into proteins, that determine the way cells live, function and even die. It was demonstrated that cells with identical genomes exposed to the same environment can differ in their protein composition and therefore phenotypes. Protein levels can vary between cells due to the stochastic nature of intracellular biochemical events, indicating that the genotype-phenotype connection is not deterministic at the cellular level. We asked whether genomes could encode isogenic cell populations more reliably than single cells. To address this question, we built two gene circuits to control three cell population-level characteristics: gene expression mean, coefficient of variation and non-genetic memory of previous expression states. Indeed, we found that these population-level characteristics were more predictable than the gene expression of single cells in a well-controlled environment.

Nevozhay, Dmitry; Adams, Rhys; van Itallie, Elizabeth; Bennett, Matthew; Balazsi, Gabor

2011-03-01

207

Regulation of Gene Expression in Protozoa Parasites  

PubMed Central

Infections with protozoa parasites are associated with high burdens of morbidity and mortality across the developing world. Despite extensive efforts to control the transmission of these parasites, the spread of populations resistant to drugs and the lack of effective vaccines against them contribute to their persistence as major public health problems. Parasites should perform a strict control on the expression of genes involved in their pathogenicity, differentiation, immune evasion, or drug resistance, and the comprehension of the mechanisms implicated in that control could help to develop novel therapeutic strategies. However, until now these mechanisms are poorly understood in protozoa. Recent investigations into gene expression in protozoa parasites suggest that they possess many of the canonical machineries employed by higher eukaryotes for the control of gene expression at transcriptional, posttranscriptional, and epigenetic levels, but they also contain exclusive mechanisms. Here, we review the current understanding about the regulation of gene expression in Plasmodium sp., Trypanosomatids, Entamoeba histolytica and Trichomonas vaginalis. PMID:20204171

Gomez, Consuelo; Esther Ramirez, M.; Calixto-Galvez, Mercedes; Medel, Olivia; Rodríguez, Mario A.

2010-01-01

208

Polyploidization and Gene Expression in Medicago sativa  

Microsoft Academic Search

\\u000a Polyploidization is a common event in plant evolution and can influence economically important traits. Modifications of gene\\u000a expression and\\/or DNA sequence are known to occur as a consequence of polyploidization. To gain insight into the effects of\\u000a sexual polyploidization on gene expression in alfalfa, we have used two diploid (2x=16) plants of the subspecies falcata and coerulea that produce 2n

Stefano Capomaccio; Fabio Veronesi; Daniele Rosellini

209

Gene expression profiling in neurological disorders  

Microsoft Academic Search

Neurological disease arises when a sufficient number of neural cells stop performing their normal functions, lose their ability\\u000a to respond to local environment, and die. In the last decade, a major technological leap led to the development of efficient\\u000a and cost-effective high-throughput methods for determining gene expression. This, in turn, resulted in the rapid accumulation\\u000a of data describing gene expression

Sergio E. Baranzini

2004-01-01

210

Deciphering Development: Quantifying Gene Expression through Imaging  

NSDL National Science Digital Library

This article from BioScience provides information on genetic tagging and how it can provide imaging in live animals. Scientists can now visualize developmental gene expression quantitatively in three dimensions and at single-cell resolution. Recent advances in optical microscopy and fluorescent genetic tags allow imaging of gene expression in live animals, as well. Eventually, researchers hope to construct virtual atlases of animal development.

Melissa Lee Philips (; )

2007-08-01

211

Protein structure protection commits gene expression patterns  

Microsoft Academic Search

BACKGROUND: Gene co-expressions often determine module-defining spatial and temporal concurrences of proteins. Yet, little effort has been devoted to tracing coordinating signals for expression correlations to the three-dimensional structures of gene products. RESULTS: We performed a global structure-based analysis of the yeast and human proteomes and contrasted this information against their respective transcriptome organizations obtained from comprehensive microarray data. We

Jianping Chen; Han Liang; Ariel Fernández

2008-01-01

212

Custom Design of a GeXP Multiplexed Assay Used to Assess Expression Profiles of Inflammatory Gene Targets in Normal Colon, Polyp, and Tumor Tissue  

PubMed Central

Colon cancers are characterized by aberrant gene expression signatures associated with disease initiation and progression. Identification of aberrant gene expression associated with colon carcinogenesis has increased significantly with application of gene array technologies. Downstream processing of these data has been hindered by the lack of robust multiplexed gene quantitative technologies facilitating study of the identified multiple gene targets. The GenomeLab Genetic Analysis System presents a novel technology platform for quantitative multiplexed gene expression analysis. This report describes the custom design of a GeXP multiplexed assay used to assess expression profiles of 14 inflammatory gene targets in normal, polyp, and tumor tissue. Characteristic normal, polyp, and tumor tissue gene expression profiles were obtained. Statistical analysis confirmed comparable relative quantitation of gene expression using the GeXP, macroarray, and single-plex real-time polymerase chain reaction assays. GeXP assays may be usefully applied in clinical and regulatory studies of multiple gene targets. This system permits custom-design options for relative quantification of multiple gene target expression, simultaneously in a single reaction, using nanogram quantities of total RNA template. The system provides an approach to advance the study of multiple targets identified from gene array analysis with potential for characterizing gene expression signatures in clinical diagnostics. PMID:21354059

Drew, Janice E.; Mayer, Claus-Dieter; Farquharson, Andrew J.; Young, Pauline; Barrera, Lawrence N.

2011-01-01

213

Potassium channel ether ŕ go-go1 is aberrantly expressed in human liposarcoma and promotes tumorigenesis.  

PubMed

The ether ŕ go-go1 (Eag1) channel is overexpressed in a variety of cancers. However, the expression and function of Eag1 in liposarcoma are poorly understood. In the present study, the mRNA expression of Eag1 in different adipose tissue samples was examined by real-time PCR. Then, the protein expression of Eag1 in 131 different adipose tissues from 109 patients was detected by immunohistochemistry. Next, the associations between Eag1 expression and clinicopathological features of liposarcoma were analyzed. In addition, the effects of Eag1 on liposarcoma cell proliferation and cycle were evaluated by CCK-8, colony formation, xenograft mouse model, and flow cytometry, respectively. Finally, the activation of p38 mitogen-activated protein kinase (MAPK) was detected by Western blot analysis to explain the detailed mechanisms of oncogenic potential of Eag1 in liposarcoma. It was found that Eag1 was aberrantly expressed in over 67% liposarcomas, with a higher frequency than in lipoma, hyperplasia, inflammation, and normal adipose tissues. However, Eag1 expression was not correlated with clinicopathological features of liposarcoma. Eag1 inhibitor imipramine or Eag1-shRNA significantly suppressed the proliferation of liposarcoma cells in vitro and in vivo, accompanying with accumulation of cells in the G1 phase. These results suggest that Eag1 plays an important role in regulating the proliferation and cell cycle of liposarcoma cells and might be a potential therapeutic target for liposarcoma. PMID:25136578

Wu, Jin; Zhong, Daixing; Wei, Yujian; Wu, Xinyu; Kang, Liangqi; Ding, Zhenqi

2014-01-01

214

Potassium Channel Ether ŕ go-go1 Is Aberrantly Expressed in Human Liposarcoma and Promotes Tumorigenesis  

PubMed Central

The ether ŕ go-go1 (Eag1) channel is overexpressed in a variety of cancers. However, the expression and function of Eag1 in liposarcoma are poorly understood. In the present study, the mRNA expression of Eag1 in different adipose tissue samples was examined by real-time PCR. Then, the protein expression of Eag1 in 131 different adipose tissues from 109 patients was detected by immunohistochemistry. Next, the associations between Eag1 expression and clinicopathological features of liposarcoma were analyzed. In addition, the effects of Eag1 on liposarcoma cell proliferation and cycle were evaluated by CCK-8, colony formation, xenograft mouse model, and flow cytometry, respectively. Finally, the activation of p38 mitogen-activated protein kinase (MAPK) was detected by Western blot analysis to explain the detailed mechanisms of oncogenic potential of Eag1 in liposarcoma. It was found that Eag1 was aberrantly expressed in over 67% liposarcomas, with a higher frequency than in lipoma, hyperplasia, inflammation, and normal adipose tissues. However, Eag1 expression was not correlated with clinicopathological features of liposarcoma. Eag1 inhibitor imipramine or Eag1-shRNA significantly suppressed the proliferation of liposarcoma cells in vitro and in vivo, accompanying with accumulation of cells in the G1 phase. These results suggest that Eag1 plays an important role in regulating the proliferation and cell cycle of liposarcoma cells and might be a potential therapeutic target for liposarcoma. PMID:25136578

Wu, Jin; Zhong, Daixing; Wei, Yujian; Wu, Xinyu; Kang, Liangqi; Ding, Zhenqi

2014-01-01

215

Candidate genes for panhypopituitarism identified by gene expression profiling  

PubMed Central

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease. PMID:21828248

Mortensen, Amanda H.; MacDonald, James W.; Ghosh, Debashis

2011-01-01

216

Homeobox genes expressed during echinoderm arm regeneration.  

PubMed

Regeneration in echinoderms has proved to be more amenable to study in the laboratory than the more classical vertebrate models, since the smaller genome size and the absence of multiple orthologs for different genes in echinoderms simplify the analysis of gene function during regeneration. In order to understand the role of homeobox-containing genes during arm regeneration in echinoderms, we isolated the complement of genes belonging to the Hox class that are expressed during this process in two major echinoderm groups: asteroids (Echinaster sepositus and Asterias rubens) and ophiuroids (Amphiura filiformis), both of which show an extraordinary capacity for regeneration. By exploiting the sequence conservation of the homeobox, putative orthologs of several Hox genes belonging to the anterior, medial, and posterior groups were isolated. We also report the isolation of a few Hox-like genes expressed in the same systems. PMID:24309817

Ben Khadra, Yousra; Said, Khaled; Thorndyke, Michael; Martinez, Pedro

2014-04-01

217

Gene Expression Patterns in Ovarian Carcinomas  

Microsoft Academic Search

We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly

Marci E. Schaner; Douglas T. Ross; Giuseppe Ciaravino; Therese Sřrlie; Olga Troyanskaya; Maximilian Diehn; Yan C. Wang; George E. Duran; Thomas L. Sikic; Sandra Caldeira; Hanne Skomedal; I-Ping Tu; Tina Hernandez-Boussard; Steven W. Johnson; Peter J. O'Dwyer; Michael J. Fero; Gunnar B. Kristensen; Anne-Lise Břrresen-Dale; Trevor Hastie; Robert Tibshirani; Matt van de Rijn; Nelson N. Teng; Teri A. Longacre; David Botstein; Patrick O. Brown; Branimir I. Sikic

2003-01-01

218

Molecular mechanisms of collagen gene expression  

Microsoft Academic Search

Collagens are a structurally and functionally heterogenous group of proteins encoded by a family of genes that share evolutionary history. Collagen gene expression is regulated both in developmental, tissue-specific manners as well as in response to a variety of biologic and pharmacologic inducers. In the present review we have attempted to synthesize a conceptual overview of the available information from

Rajendra Raghow; James P. Thompson

1989-01-01

219

EXPERIMENTAL Differential Gene Expression between Juvenile  

E-print Network

Genes Play a Role in the Regeneration of Membranous Bone Derrick C. Wan, M.D. Oliver O. Aalami, M-transcriptase polymerase chain reaction confirmation of selected genes--BMP-2, BMP-4, and BMP-7; and osteopontin (OP amounts of BMP-2 and OP. Minimal difference in OC expression was observed between juvenile and adult dura

Derynck, Rik

220

Polyunsaturated fatty acids and gene expression  

Technology Transfer Automated Retrieval System (TEKTRAN)

Purpose of review. This review focuses on the effect(s) of n-3 polyunsaturated fatty acids (PUFA) on gene transcription as determined from data generated using cDNA microarrays. Introduced within the past decade, this methodology allows detection of the expression of thousands of genes simultaneo...

221

Perspectives: Gene Expression in Fisheries Management  

USGS Publications Warehouse

Functional genes and gene expression have been connected to physiological traits linked to effective production and broodstock selection in aquaculture, selective implications of commercial fish harvest, and adaptive changes reflected in non-commercial fish populations subject to human disturbance and climate change. Gene mapping using single nucleotide polymorphisms (SNPs) to identify functional genes, gene expression (analogue microarrays and real-time PCR), and digital sequencing technologies looking at RNA transcripts present new concepts and opportunities in support of effective and sustainable fisheries. Genomic tools have been rapidly growing in aquaculture research addressing aspects of fish health, toxicology, and early development. Genomic technologies linking effects in functional genes involved in growth, maturation and life history development have been tied to selection resulting from harvest practices. Incorporating new and ever-increasing knowledge of fish genomes is opening a different perspective on local adaptation that will prove invaluable in wild fish conservation and management. Conservation of fish stocks is rapidly incorporating research on critical adaptive responses directed at the effects of human disturbance and climate change through gene expression studies. Genomic studies of fish populations can be generally grouped into three broad categories: 1) evolutionary genomics and biodiversity; 2) adaptive physiological responses to a changing environment; and 3) adaptive behavioral genomics and life history diversity. We review current genomic research in fisheries focusing on those that use microarrays to explore differences in gene expression among phenotypes and within or across populations, information that is critically important to the conservation of fish and their relationship to humans.

Nielsen, Jennifer L.; Pavey, Scott A.

2010-01-01

222

Mechanisms of control of gene expression  

SciTech Connect

This book examines an array of topics on the regulation of gene expression, including an examination of DNA-protein interactions and the role of oncogene proteins in normal and abnormal cellular responses. The book focuses on the control of mRNA transcription in eykaryotes and delineates other areas including gene regulation in prokaryotes and control of stable RNA synthesis.

Cullen, B.; Gage, L.P.; Siddiqui, M.A.Q.; Skalka, A.M.; Weissbach, H.

1987-01-01

223

Histone Modifications Depict an Aberrantly Heterochromatinized FMR1 Gene in Fragile X Syndrome  

PubMed Central

Fragile X syndrome is caused by an expansion of a polymorphic CGG triplet repeat that results in silencing of FMR1 expression. This expansion triggers methylation of FMR1's CpG island, hypoacetylation of associated histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene. Here, we show that there is a graded spectrum of histone H4 acetylation that is proportional to CGG repeat length and that correlates with responsiveness of the gene to DNA demethylation but not with chromatin condensation. We also identify alterations in patient cells of two recently identified histone H3 modifications: methylation of histone H3 at lysine 4 and methylation of histone H3 at lysine 9, which are marks for euchromatin and heterochromatin, respectively. In fragile X cells, there is a decrease in methylation of histone H3 at lysine 4 with a large increase in methylation at lysine 9, a change that is consistent with the model of FMR1's switch from euchromatin to heterochromatin in the disease state. The high level of histone H3 methylation at lysine 9 may account for the failure of H3 to be acetylated after treatment of fragile X cells with inhibitors of histone deacetylases, a treatment that fully restores acetylation to histone H4. Using 5-aza-2?-deoxycytidine, we show that DNA methylation is tightly coupled to the histone modifications associated with euchromatin but not to the heterochromatic mark of methylation of histone H3 at lysine 9, consistent with recent findings that this histone modification may direct DNA methylation. Despite the drug-induced accumulation of mRNA in patient cells to 35% of the wild-type level, FMR1 protein remained undetectable. The identification of intermediates in the heterochromatinization of FMR1 has enabled us to begin to dissect the epigenetics of silencing of a disease-related gene in its natural chromosomal context. PMID:12232854

Coffee, Bradford; Zhang, Fuping; Ceman, Stephanie; Warren, Stephen T.; Reines, Daniel

2002-01-01

224

Histone modifications depict an aberrantly heterochromatinized FMR1 gene in fragile x syndrome.  

PubMed

Fragile X syndrome is caused by an expansion of a polymorphic CGG triplet repeat that results in silencing of FMR1 expression. This expansion triggers methylation of FMR1's CpG island, hypoacetylation of associated histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene. Here, we show that there is a graded spectrum of histone H4 acetylation that is proportional to CGG repeat length and that correlates with responsiveness of the gene to DNA demethylation but not with chromatin condensation. We also identify alterations in patient cells of two recently identified histone H3 modifications: methylation of histone H3 at lysine 4 and methylation of histone H3 at lysine 9, which are marks for euchromatin and heterochromatin, respectively. In fragile X cells, there is a decrease in methylation of histone H3 at lysine 4 with a large increase in methylation at lysine 9, a change that is consistent with the model of FMR1's switch from euchromatin to heterochromatin in the disease state. The high level of histone H3 methylation at lysine 9 may account for the failure of H3 to be acetylated after treatment of fragile X cells with inhibitors of histone deacetylases, a treatment that fully restores acetylation to histone H4. Using 5-aza-2'-deoxycytidine, we show that DNA methylation is tightly coupled to the histone modifications associated with euchromatin but not to the heterochromatic mark of methylation of histone H3 at lysine 9, consistent with recent findings that this histone modification may direct DNA methylation. Despite the drug-induced accumulation of mRNA in patient cells to 35% of the wild-type level, FMR1 protein remained undetectable. The identification of intermediates in the heterochromatinization of FMR1 has enabled us to begin to dissect the epigenetics of silencing of a disease-related gene in its natural chromosomal context. PMID:12232854

Coffee, Bradford; Zhang, Fuping; Ceman, Stephanie; Warren, Stephen T; Reines, Daniel

2002-10-01

225

Genetics of Gene Expression in CNS  

PubMed Central

Transcriptome studies have revealed a surprisingly high level of variation among individuals in expression of key genes in the CNS under both normal and experimental conditions. Ten-fold variation is common, yet the specific causes and consequences of this variation are largely unknown. By combining classic gene mapping methods—family linkage studies and genome-wide association—with high-throughput genomics it is now possible to define quantitative trait loci (QTLs), single gene variants, and even single SNPs and indels that control gene expression in different brain regions and cells. This review considers some of the major technical and conceptual challenges in analyzing variation in expression in the CNS with a focus on mRNAs, rather than non-coding RNAs or proteins. At one level of analysis this work has been highly successful, and we finally have techniques that can be used to track down small numbers of loci that control expression in the CNS. But at a higher level of analysis, we still do not understand the genetic architecture of gene expression in brain, the consequences of expression QTLs (eQTLs) on protein levels or on cell function, or the combined impact of expression differences on behavior and disease risk. These important gaps are likely to be bridged over the next several decades using 1. much larger sample sizes, 2. more powerful RNA sequencing and proteomic methods, and 3. novel statistical and computational models to predict genome-to-phenome relations. PMID:25172476

Pandey, Ashutosh K.; Williams, Robert W.

2014-01-01

226

Control of gene expression in trypanosomes.  

PubMed Central

Trypanosomes are protozoan agents of major parasitic diseases such as Chagas' disease in South America and sleeping sickness of humans and nagana disease of cattle in Africa. They are transmitted to mammalian hosts by specific insect vectors. Their life cycle consists of a succession of differentiation and growth phases requiring regulated gene expression to adapt to the changing extracellular environment. Typical of such stage-specific expression is that of the major surface antigens of Trypanosoma brucei, procyclin in the procyclic (insect) form and the variant surface glycoprotein (VSG) in the bloodstream (mammalian) form. In trypanosomes, the regulation of gene expression is effected mainly at posttranscriptional levels, since primary transcription of most of the genes occurs in long polycistronic units and is constitutive. The transcripts are processed by transsplicing and polyadenylation under the influence of intergenic polypyrimidine tracts. These events show some developmental regulation. Untranslated sequences of the mRNAs seem to play a prominent role in the stage-specific control of individual gene expression, through a modulation of mRNA abundance. The VSG and procyclin transcription units exhibit particular features that are probably related to the need for a high level of expression. The promoters and RNA polymerase driving the expression of these units resemble those of the ribosomal genes. Their mutually exclusive expression is ensured by controls operating at several levels, including RNA elongation. Antigenic variation in the bloodstream is achieved through DNA rearrangements or alternative activation of the telomeric VSG gene expression sites. Recent discoveries, such as the existence of a novel nucleotide in telomeric DNA and the generation of point mutations in VSG genes, have shed new light on the mechanisms and consequences of antigenic variation. PMID:7603410

Vanhamme, L; Pays, E

1995-01-01

227

Application of multidisciplinary analysis to gene expression.  

SciTech Connect

Molecular analysis of cancer, at the genomic level, could lead to individualized patient diagnostics and treatments. The developments to follow will signal a significant paradigm shift in the clinical management of human cancer. Despite our initial hopes, however, it seems that simple analysis of microarray data cannot elucidate clinically significant gene functions and mechanisms. Extracting biological information from microarray data requires a complicated path involving multidisciplinary teams of biomedical researchers, computer scientists, mathematicians, statisticians, and computational linguists. The integration of the diverse outputs of each team is the limiting factor in the progress to discover candidate genes and pathways associated with the molecular biology of cancer. Specifically, one must deal with sets of significant genes identified by each method and extract whatever useful information may be found by comparing these different gene lists. Here we present our experience with such comparisons, and share methods developed in the analysis of an infant leukemia cohort studied on Affymetrix HG-U95A arrays. In particular, spatial gene clustering, hyper-dimensional projections, and computational linguistics were used to compare different gene lists. In spatial gene clustering, different gene lists are grouped together and visualized on a three-dimensional expression map, where genes with similar expressions are co-located. In another approach, projections from gene expression space onto a sphere clarify how groups of genes can jointly have more predictive power than groups of individually selected genes. Finally, online literature is automatically rearranged to present information about genes common to multiple groups, or to contrast the differences between the lists. The combination of these methods has improved our understanding of infant leukemia. While the complicated reality of the biology dashed our initial, optimistic hopes for simple answers from microarrays, we have made progress by combining very different analytic approaches.

Wang, Xuefel (University of New Mexico, Albuquerque, NM); Kang, Huining (University of New Mexico, Albuquerque, NM); Fields, Chris (New Mexico State University, Las Cruces, NM); Cowie, Jim R. (New Mexico State University, Las Cruces, NM); Davidson, George S.; Haaland, David Michael; Sibirtsev, Valeriy (New Mexico State University, Las Cruces, NM); Mosquera-Caro, Monica P. (University of New Mexico, Albuquerque, NM); Xu, Yuexian (University of New Mexico, Albuquerque, NM); Martin, Shawn Bryan; Helman, Paul (University of New Mexico, Albuquerque, NM); Andries, Erik (University of New Mexico, Albuquerque, NM); Ar, Kerem (University of New Mexico, Albuquerque, NM); Potter, Jeffrey (University of New Mexico, Albuquerque, NM); Willman, Cheryl L. (University of New Mexico, Albuquerque, NM); Murphy, Maurice H. (University of New Mexico, Albuquerque, NM)

2004-01-01

228

Identification of suitable endogenous control genes for microRNA gene expression analysis in human breast cancer  

PubMed Central

The discovery of microRNAs (miRNAs) added an extra level of intricacy to the already complex system regulating gene expression. These single-stranded RNA molecules, 18–25 nucleotides in length, negatively regulate gene expression through translational inhibition or mRNA cleavage. The discovery that aberrant expression of specific miRNAs contributes to human disease has fueled much interest in profiling the expression of these molecules. Real-time quantitative PCR (RQ-PCR) is a sensitive and reproducible gene expression quantitation technique which is now being used to profile miRNA expression in cells and tissues. To correct for systematic variables such as amount of starting template, RNA quality and enzymatic efficiencies, RQ-PCR data is commonly normalised to an endogenous control (EC) gene, which ideally, is stably-expressed across the test sample set. A universal endogenous control suitable for every tissue type, treatment and disease stage has not been identified and is unlikely to exist, so, to avoid introducing further error in the quantification of expression data it is necessary that candidate ECs be validated in the samples of interest. While ECs have been validated for quantification of mRNA expression in various experimental settings, to date there is no report of the validation of miRNA ECs for expression profiling in breast tissue. In this study, the expression of five miRNA genes (let-7a, miR-10b, miR-16, miR-21 and miR-26b) and three small nucleolar RNA genes (RNU19, RNU48 and Z30) was examined across malignant, benign and normal breast tissues to determine the most appropriate normalisation strategy. This is the first study to identify reliable ECs for analysis of miRNA by RQ-PCR in human breast tissue. PMID:18718003

Davoren, Pamela A; McNeill, Roisin E; Lowery, Aoife J; Kerin, Michael J; Miller, Nicola

2008-01-01

229

SAGEmap: a public gene expression resource.  

PubMed

We have constructed a public gene expression data repository and online data access and analysis, WWW and FTP sites for serial analysis of gene expression (SAGE) data. The WWW and FTP components of this resource, SAGEmap, are located at http://www.ncbi.nlm.nih. gov/sage and ftp://ncbi.nlm.nih.gov/pub/sage, respectively. We herein describe SAGE data submission procedures, the construction and characteristics of SAGE tags to gene assignments, the derivation and use of a novel statistical test designed specifically for differential-type analyses of SAGE data, and the organization and use of this resource. PMID:10899154

Lash, A E; Tolstoshev, C M; Wagner, L; Schuler, G D; Strausberg, R L; Riggins, G J; Altschul, S F

2000-07-01

230

Aberrant Upregulation of 14-3-3? and EZH2 Expression Serves as an Inferior Prognostic Biomarker for Hepatocellular Carcinoma  

PubMed Central

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world. It is of important significance to find biomarkers for the prognostic monitoring of HCC. The 14-3-3? and EZH2 proteins are involved in cell cycle regulation and epigenetic silencing. We herein examined the significance of 14-3-3 ? and EZH2 in HCC (n?=?167) by immunohistochemistry, RT-PCR and qRT-PCR. The correlation between 14-3-3? and EZH2 expression and patients' clinicopathologic features were examined, as was the correlation between 14-3-3? and EZH2 expression and the prognosis of HCC patients. We found that 14-3-3? and EZH2 were highly expressed in HCC (71% and 90%), the expression of EZH2, but not 14-3-3?, is associated with vascular invasion and tumor differentiation (p<0.01). The coexistence of 14-3-3? and EZH2 overexpression is associated with a relatively unfavorable prognosis (p<0.01), suggesting that aberrant upregulation of 14-3-3? and EZH2 expression serves as an inferior prognostic biomarker for HCC. PMID:25226601

Zhang, Yi; Li, Yang; Lin, Changwei; Ding, Jie; Liao, Guoqing; Tang, Bo

2014-01-01

231

Kallikrein-related peptidase 7 (KLK7) is a proliferative factor that is aberrantly expressed in human colon cancer.  

PubMed

Emerging evidence indicates that serine proteases of the tissue kallikrein-related peptidases family (KLK) are implicated in tumorigenesis. We recently reported the ectopic expression of KLK4 and KLK14 in colonic cancers and their signaling to control cell proliferation. Human tissue kallikrein-related peptidase 7 (KLK7) is often dysregulated in many cancers; however, its role in colon tumorigenesis has not yet been established. In the present study, we analyzed expression of KLK7 in 15 colon cancer cell lines and in 38 human colonic tumors. In many human colon cancer cells, KLK7 mRNA was observed, which leads to KLK7 protein expression and secretion. Furthermore, KLK7 was detected in human colon adenocarcinomas, but it was absent in normal epithelia. KLK7 overexpression in HT29 colon cancer cells upon stable transfection with a KLK7 expression plasmid resulted in increased cell proliferation. Moreover, subcutaneous inoculation of transfected cells into nude mice led to increased tumor growth that was associated with increased tumor cell proliferation as reflected by a positive Ki-67 staining. Our results demonstrate the aberrant expression of KLK7 in colon cancer cells and tissues and its involvement in cell proliferation in vitro and in vivo. Thus, KLK7 may represent a potential therapeutic target for human colon tumorigenesis. PMID:25153388

Walker, Francine; Nicole, Pascal; Jallane, Abdelhak; Soosaipillai, Antoninus; Mosbach, Valentine; Oikonomopoulou, Katerina; Diamandis, Eleftherios P; Magdolen, Viktor; Darmoul, Dalila

2014-09-01

232

Aberrant 3? splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization  

PubMed Central

The frequency distribution of mutation-induced aberrant 3? splice sites (3?ss) in exons and introns is more complex than for 5? splice sites, largely owing to sequence constraints upstream of intron/exon boundaries. As a result, prediction of their localization remains a challenging task. Here, nucleotide sequences of previously reported 218 aberrant 3?ss activated by disease-causing mutations in 131 human genes were compared with their authentic counterparts using currently available splice site prediction tools. Each tested algorithm distinguished authentic 3?ss from cryptic sites more effectively than from de novo sites. The best discrimination between aberrant and authentic 3?ss was achieved by the maximum entropy model. Almost one half of aberrant 3?ss was activated by AG-creating mutations and ?95% of the newly created AGs were selected in vivo. The overall nucleotide structure upstream of aberrant 3?ss was characterized by higher purine content than for authentic sites, particularly in position ?3, that may be compensated by more stringent requirements for positive and negative nucleotide signatures centred around position ?11. A newly developed online database of aberrant 3?ss will facilitate identification of splicing mutations in a gene or phenotype of interest and future optimization of splice site prediction tools. PMID:16963498

Vo?echovský, Igor

2006-01-01

233

Microarray analysis of gene expression in parthenotes and in vitro-derived goat embryos.  

PubMed

The present work was carried out to investigate the global gene expression profile to search differentially expressed candidate transcripts between parthenogenetic and in vitro-fertilized (IVF) caprine morula. For this study, total RNA was isolated from diploid parthenogenetic and IVF embryos, and complementary DNA was synthesized. Microarray and relative real-time polymerase chain reaction analysis were performed to check global gene expression profile and validation, respectively. According to the microarray analysis, the total number of upregulated (UR) and downregulated (DR) genes was 613 and 220, respectively in diploid parthenogenetic morula as compared with IVF morula. The number of genes showing about two-, two- to five-, five- to 10-, 10- to 20-, and above 20-fold UR and DR genes was 147, 229, 122, 59, and 56 and 94, 73, 18, 13, and 22, respectively. Five UR genes validated (PTEN, PHF3, CTNNB1, SELK, and NPDC1) and all of them were significantly higher in parthenotes, which was in accordance with microarray results, whereas the expression of DR (AURKC and KLF15) genes were downregulated in parthenotes as observed in microarray results but the difference was not significant (P < 0.05). In conclusion, our findings demonstrate differential expression of a large number of genes in parthenotes compared with IVF embryos, which may be the reason for aberrant parthenogenetic embryo development in caprine species. PMID:24507961

Singh, Renu; Kumar, Kuldeep; Mahapatra, P S; Kumar, Manish; Agarwal, Pranjali; Bhure, S K; Malakar, Dhruba; Bhanja, S K; Bag, Sadhan

2014-04-01

234

Reference gene screening for analyzing gene expression across goat tissue.  

PubMed

Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken. PMID:25049756

Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai

2013-12-01

235

Reference Gene Screening for Analyzing Gene Expression Across Goat Tissue  

PubMed Central

Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken. PMID:25049756

Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai

2013-01-01

236

Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.  

PubMed

Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth. PMID:18003899

Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

2007-11-20

237

Patterns of Gene Expression in Drosophila Embryogenesis  

NSDL National Science Digital Library

A new image database of gene expression patterns in Drosophila embryogenesis is now available from the Berkeley Drosophila Genome Project (BDGP), a consortium of the Drosophila Genome Center. The BDGP team used "high throughput 96-well plate RNA in situ protocol to determine patterns of gene expression during embryogenesis for Drosophila genes represented in non-redundant sets of Drosophila ESTs DGC1 and DGC2." The entire set of image, microarray, and annotation data may be browsed or searched from this Web site. As of October 4, 2002, 1354 gene expressions have been documented with 25,263 digital photographs, with many more additions expected. This site also provides a useful FAQs page.

238

Differential gene expression during multistage carcinogenesis  

SciTech Connect

The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of the Harvey-ras proto-oncogene has been found to be an early event associated with the initiation of mouse skin tumors by the polycyclic aromatic hydrocarbon 7,12 dimethylbenz(a)anthracene and the pure initiator ethyl carbamate (urethane). In contrast to chemical initiation of mouse skin tumors, ionizing radiation-initiated malignant skin tumors have been shown to possess distinct non-ras transforming gene(s). Differential screening of cDNA libraries made from chemically initiated malignant skin tumors has been used to identify a number of cellular gene transcripts that are overexpressed during mouse skin tumor progression. These differentially expressed genes include {beta}-actin, ubiquitin, a hyperproliferative keratin (K6), a gene whose product is a member of a fatty acid or lipid-binding protein family, and a gene called transin or stromelysin. The overexpression of the stromelysin gene, which encodes a metalloproteinase that degrades proteins in the basement membrane, is hypothesized to play a functional role in malignant tumor cell invasion and metastasis. The authors believe that the cloning, identification, and characterization of gene sequences that are differentially expressed during tumor progression could lead to the discovery of gene products that either play functional roles in skin tumor progression or in the maintenance of various progressive tumor phenotypes.

Bowden, G.T. (Univ. of Arizona Medical School, Tucson (United States)); Krieg, P. (German Cancer Research Center, Heidelberg (West Germany))

1991-06-01

239

A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report  

PubMed Central

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level, multiple factors using diverse biochemical and molecular pathways have been recognized. Succinct recognition and classification of clinical disease subsets, as well as the availability of disease biomarkers, remains largely unsolved. Based on information produced by the present authors’ and other laboratories, a lupus gene expression array consisting of 30 genes, previously claimed to contribute to aberrant function of T cells, was developed. An additional eight genes were included as controls. Peripheral blood was obtained from 10 patients (19 samples) with SLE and six patients with rheumatoid arthritis (RA) as well as 19 healthy controls. T cell mRNA was subjected to reverse transcription and PCR, and the gene expression levels were measured. Conventional statistical analysis was performed along with principal component analysis (PCA) to capture the contribution of all genes to disease diagnosis and clinical parameters. The lupus gene expression array faithfully informed on the expression levels of genes. The recorded changes in expression reflect those reported in the literature by using a relatively small (5ml) amount of peripheral blood. PCA of gene expression levels placed SLE samples apart from normal and RA samples regardless of disease activity. Individual principal components tended to define specific disease manifestations such as arthritis and proteinuria. Thus, a lupus gene expression array based on genes previously claimed to contribute to immune pathogenesis of SLE may define the disease, and principal components of the expression of 30 genes may define patients with specific disease manifestations. PMID:21138984

Juang, Y-T; Peoples, C; Kafri, R; Kyttaris, VC; Sunahori, K; Kis-Toth, K; Fitzgerald, L; Ergin, S; Finnell, M; Tsokos, GC

2013-01-01

240

Paternally expressed genes predominate in the placenta  

PubMed Central

The discovery of genomic imprinting through studies of manipulated mouse embryos indicated that the paternal genome has a major influence on placental development. However, previous research has not demonstrated paternal bias in imprinted genes. We applied RNA sequencing to trophoblast tissue from reciprocal hybrids of horse and donkey, where genotypic differences allowed parent-of-origin identification of most expressed genes. Using this approach, we identified a core group of 15 ancient imprinted genes, of which 10 were paternally expressed. An additional 78 candidate imprinted genes identified by RNA sequencing also showed paternal bias. Pyrosequencing was used to confirm the imprinting status of six of the genes, including the insulin receptor (INSR), which may play a role in growth regulation with its reciprocally imprinted ligand, histone acetyltransferase-1 (HAT1), a gene involved in chromatin modification, and lymphocyte antigen 6 complex, locus G6C, a newly identified imprinted gene in the major histocompatibility complex. The 78 candidate imprinted genes displayed parent-of-origin expression bias in placenta but not fetus, and most showed less than 100% silencing of the imprinted allele. Some displayed variability in imprinting status among individuals. This variability results in a unique epigenetic signature for each placenta that contributes to variation in the intrauterine environment and thus presents the opportunity for natural selection to operate on parent-of-origin differential regulation. Taken together, these features highlight the plasticity of imprinting in mammals and the central importance of the placenta as a target tissue for genomic imprinting. PMID:23754418

Wang, Xu; Miller, Donald C.; Harman, Rebecca; Antczak, Douglas F.; Clark, Andrew G.

2013-01-01

241

Noise minimization in eukaryotic gene expression  

SciTech Connect

All organisms have elaborate mechanisms to control rates of protein production. However, protein production is also subject to stochastic fluctuations, or noise. Several recent studies in Saccharomyces cerevisiae and Escherichia coli have investigated the relationship between transcription and translation rates and stochastic fluctuations in protein levels, or more generally, how such randomness is a function of intrinsic and extrinsic factors. However, the fundamental question of whether stochasticity in protein expression is generally biologically relevant has not been addressed, and it remains unknown whether random noise in the protein production rate of most genes significantly affects the fitness of any organism. We propose that organisms should be particularly sensitive to variation in the protein levels of two classes of genes: genes whose deletion is lethal to the organism and genes that encode subunits of multiprotein complexes. Using an experimentally verified model of stochastic gene expression in S. cerevisiae, we estimate the noise in protein production for nearly every yeast gene, and confirm our prediction that the production of essential and complex-forming proteins involves lower levels of noise than does the production of most other genes. Our results support the hypothesis that noise in gene expression is a biologically important variable, is generally detrimental to organismal fitness, and is subject to natural selection.

Fraser, Hunter B.; Hirsh, Aaron E.; Giaever, Guri; Kumm, Jochen; Eisen, Michael B.

2004-01-15

242

Structure, evolution and expression of insulin genes  

SciTech Connect

Since the initial discovery of insulin by Banting and Best in 1922 enoromous progress has been made in understanding the role of this hormone in the control of diabetes and in regulating glucose homeostasis in vertebrates. However, until very recently, little was known abut the structure of the insulin genes or the control of insulin gene expression in the normal and pathological state. We have been studying the structure of the rat and human genes encoding preproinsulin and the chromosomal location of the human gene. In addition, we have reintroduced the isolated insulin genes into mammalian cells growning in culture in order to study the molecular events associated with insulin expression. A summary of our recent findings is reported here.

Cordell, B.; Lebo, R.V.; Yu, L.C.; Lau, Y.F.; Carrano, A.V.; Goodman, H.M.

1980-01-01

243

Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients.  

PubMed

The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability. PMID:19759560

Iacobucci, I; Lonetti, A; Messa, F; Ferrari, A; Cilloni, D; Soverini, S; Paoloni, F; Arruga, F; Ottaviani, E; Chiaretti, S; Messina, M; Vignetti, M; Papayannidis, C; Vitale, A; Pane, F; Piccaluga, P P; Paolini, S; Berton, G; Baruzzi, A; Saglio, G; Baccarani, M; Foŕ, R; Martinelli, G

2010-01-01

244

Methylomics of gene expression in human monocytes.  

PubMed

DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3' UTR, gene bodies, CpG shores or 'offshore' sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10(-308)) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases. PMID:23900078

Liu, Yongmei; Ding, Jingzhong; Reynolds, Lindsay M; Lohman, Kurt; Register, Thomas C; De La Fuente, Alberto; Howard, Timothy D; Hawkins, Greg A; Cui, Wei; Morris, Jessica; Smith, Shelly G; Barr, R Graham; Kaufman, Joel D; Burke, Gregory L; Post, Wendy; Shea, Steven; McCall, Charles E; Siscovick, David; Jacobs, David R; Tracy, Russell P; Herrington, David M; Hoeschele, Ina

2013-12-15

245

Methylomics of gene expression in human monocytes  

PubMed Central

DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3? UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10?308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases. PMID:23900078

Liu, Yongmei; Ding, Jingzhong; Reynolds, Lindsay M.; Lohman, Kurt; Register, Thomas C.; De La Fuente, Alberto; Howard, Timothy D.; Hawkins, Greg A.; Cui, Wei; Morris, Jessica; Smith, Shelly G.; Barr, R. Graham; Kaufman, Joel D.; Burke, Gregory L.; Post, Wendy; Shea, Steven; Mccall, Charles E.; Siscovick, David; Jacobs, David R.; Tracy, Russell P.; Herrington, David M.; Hoeschele, Ina

2013-01-01

246

Phytochrome-regulated Gene Expression  

Technology Transfer Automated Retrieval System (TEKTRAN)

Identification of all genes involved in the phytochrome (phy)- mediated responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth and development. This article highlights and integrates the central findings of two recent compr...

247

Cell lines derived from human parthenogenetic embryos can display aberrant centriole distribution and altered expression levels of mitotic spindle check-point transcripts.  

PubMed

Human parthenogenetic embryos have recently been proposed as an alternative, less controversial source of embryonic stem cell (ESC) lines; however many aspects related to the biology of parthenogenetic embryos and parthenogenetic derived cell lines still need to be elucidated. We present here results on human cell lines (HP1 and HP3) derived from blastocysts obtained by oocyte parthenogenetic activation. Cell lines showed typical ESC morphology, expressed Oct-4, Nanog, Sox-2, Rex-1, alkaline phosphatase, SSEA-4, TRA 1-81 and had high telomerase activity. Expression of genes specific for different embryonic germ layers was detected from HP cells differentiated upon embryoid body (EBs) formation. Furthermore, when cultured in appropriate conditions, HP cell lines were able to differentiate into mature cell types of the neural and hematopoietic lineages. However, the injection of undifferentiated HP cells in immunodeficient mice resulted either in poor differentiation or in tumour formation with the morphological characteristics of myofibrosarcomas. Further analysis of HP cells indicated aberrant levels of molecules related to spindle formation as well as the presence of an abnormal number of centrioles and autophagic activity. Our results confirm and extend the notion that human parthenogenetic stem cells can be derived and can differentiate in mature cell types, but also highlight the possibility that, alteration of the proliferation mechanisms may occur in these cells, suggesting great caution if a therapeutic use of this kind of stem cells is considered. PMID:20058199

Brevini, Tiziana A L; Pennarossa, Georgia; Antonini, Stefania; Paffoni, Alessio; Tettamanti, Gianluca; Montemurro, Tiziana; Radaelli, Enrico; Lazzari, Lorenza; Rebulla, Paolo; Scanziani, Eugenio; de Eguileor, Magda; Benvenisty, Nissim; Ragni, Guido; Gandolfi, Fulvio

2009-12-01

248

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.  

PubMed

Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids. PMID:23284171

Varghese, Binny V; Koohestani, Faezeh; McWilliams, Michelle; Colvin, Arlene; Gunewardena, Sumedha; Kinsey, William H; Nowak, Romana A; Nothnick, Warren B; Chennathukuzhi, Vargheese M

2013-02-01

249

Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation.  

PubMed

Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases. PMID:23755305

Pan, Dongning; Mao, Chunxiao; Wang, Yong-Xu

2013-01-01

250

Suppression of Gluconeogenic Gene Expression by LSD1-Mediated Histone Demethylation  

PubMed Central

Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases. PMID:23755305

Pan, Dongning; Mao, Chunxiao; Wang, Yong-Xu

2013-01-01

251

Heterelogous Expression of Plant Genes  

PubMed Central

Heterologous expression allows the production of plant proteins in an organism which is simpler than the natural source. This technology is widely used for large-scale purification of plant proteins from microorganisms for biochemical and biophysical analyses. Additionally expression in well-defined model organisms provides insights into the functions of proteins in complex pathways. The present review gives an overview of recombinant plant protein production methods using bacteria, yeast, insect cells, and Xenopus laevis oocytes and discusses the advantages of each system for functional studies and protein characterization. PMID:19672459

Yesilirmak, Filiz; Sayers, Zehra

2009-01-01

252

Regulatory mechanisms for floral homeotic gene expression.  

PubMed

Proper regulation of floral homeotic gene (or ABCE gene) expression ensures the development of floral organs in the correct number, type, and precise spatial arrangement. This review summarizes recent advances on the regulation of floral homeotic genes, highlighting the variety and the complexity of the regulatory mechanisms involved. As flower development is one of the most well characterized developmental processes in higher plants, it facilitates the discovery of novel regulatory mechanisms. To date, mechanisms for the regulation of floral homeotic genes range from transcription to post-transcription, from activators to repressors, and from microRNA- to ubiquitin-mediated post-transcriptional regulation. Region-specific activation of floral homeotic genes is dependent on the integration of a flower-specific activity provided by LEAFY (LFY) and a region- and stage-specific activating function provided by one of the LFY cofactors. Two types of regulatory loops, the feed-forward and the feedback loop, provide properly timed gene activation and subsequent maintenance and refinement in proper spatial and temporal domains of ABCE genes. Two different microRNA/target modules may have been independently recruited in different plant species to regulate C gene expression. Additionally, competition among different MADS box proteins for common interacting partners may represent a mechanism in whorl boundary demarcation. Future work using systems approaches and the development of non-model plants will provide integrated views on floral homeotic gene regulation and insights into the evolution of morphological diversity in flowering plants. PMID:19922812

Liu, Zhongchi; Mara, Chloe

2010-02-01

253

Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival  

PubMed Central

Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-?B, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-?, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms. This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer. PMID:21687682

Maia, Sara; Pelletier, Marc; Ding, Jixin; Hsu, Yen-Ming; Sallan, Stephen E.; Rao, Sambasiva P.; Nadler, Lee M.; Cardoso, Angelo A.

2011-01-01

254

Virus-mediated reprogramming of gene expression in plants  

Microsoft Academic Search

Plant viruses have made many significant contributions to plant biology over the years: they have provided plant researchers with functional promoters, transient expression systems and, most recently, with critical insights into the phenomenon of posttranscriptional gene silencing. Plant virus expression vectors have the ability to either overexpress genes or suppress gene expression in plants. Whereas the ‘rules’ for gene expression

John A Lindbo; Wayne P Fitzmaurice; Guy della-Cioppa

2001-01-01

255

Selective Gene Expression in Multigene Families from Yeast to Mammals  

NSDL National Science Digital Library

Cell identity is the direct consequence of the genes expressed. This STKE Review highlights the diverse mechanisms that cells use to achieve exclusive gene expression. The details of the molecular mechanism underlying yeast mating-type switching are compared and contrasted with the mechanisms involved in immunoglobulin gene expression and odorant receptor gene expression in mammals.

Jacob Z. Dalgaard (Marie Curie Research Institute; REV)

2004-10-26

256

Identifying Complex Biological Interactions based on Categorical Gene Expression Data  

Microsoft Academic Search

A novel method, MUTIC (model utilization-based clustering), is described for identifying complex interactions between genes or gene-categories based on gene expression data. The method deals with binary categorical data, which consists of a set of gene expression profiles divided into two biologically meaningful categories. It does not require data from multiple time points. Gene expression profiles are represented by feature

Ben Goertzel; Cassio Pennachin; L. de Souza Coelho; M. Mudado

2006-01-01

257

Gene expression An organism's genome is the complete  

E-print Network

1 Gene expression An organism's genome is the complete set of genes in each of its cells. Given the same genes x different genes express under different conditions Measure the levels of the various mRNAs in a cell in a specific state gene expression profile of cell in that state cell state. #12;2 DNA

Cabrera, Javier

258

Measurement of bacterial gene expression in vivo.  

PubMed Central

The complexities of bacterial gene expression during mammalian infection cannot be addressed by in vitro experiments. We know that the infected host represents a complex and dynamic environment, which is modified during the infection process, presenting a variety of stimuli to which the pathogen must respond if it is to be successful. This response involves hundreds of ivi (in vivo-induced) genes which have recently been identified in animal and cell culture models using a variety of technologies including in vivo expression technology, differential fluorescence induction, subtractive hybridization and differential display. Proteomic analysis is beginning to be used to identify IVI proteins, and has benefited from the availability of genome sequences for increasing numbers of bacterial pathogens. The patterns of bacterial gene expression during infection remain to be investigated. Are ivi genes expressed in an organ-specific or cell-type-specific fashion? New approaches are required to answer these questions. The uses of the immunologically based in vivo antigen technology system, in situ PCR and DNA microarray analysis are considered. This review considers existing methods for examining bacterial gene expression in vivo, and describes emerging approaches that should further our understanding in the future. PMID:10874733

Hautefort, I; Hinton, J C

2000-01-01

259

The Filamentous Fungal Gene Expression Database (FFGED)  

PubMed Central

Filamentous fungal gene expression assays provide essential information for understanding systemic cellular regulation. To aid research on fungal gene expression, we constructed a novel, comprehensive, free database, the Filamentous Fungal Gene Expression Database (FFGED), available at http://bioinfo.townsend.yale.edu. FFGED features user-friendly management of gene expression data, which are assorted into experimental metadata, experimental design, raw data, normalized details, and analysis results. Data may be submitted in the process of an experiment, and any user can submit multiple experiments, thus classifying the FFGED as an “active experiment” database. Most importantly, FFGED functions as a collective and collaborative platform, by connecting each experiment with similar related experiments made public by other users, maximizing data sharing among different users, and correlating diverse gene expression levels under multiple experimental designs within different experiments. A clear and efficient web interface is provided with enhancement by AJAX (Asynchronous JavaScript and XML) and through a collection of tools to effectively facilitate data submission, sharing, retrieval and visualization. PMID:20025988

Zhang, Zhang; Townsend, Jeffrey P.

2010-01-01

260

Large-Scale Serial Analysis of Gene Expression Reveals Genes Differentially Expressed in Ovarian Cancer1  

Microsoft Academic Search

Difficulties in the detection, diagnosis, and treatment of ovarian cancer result in an overall low survival rate of women with this disease. A better understanding of the pathways involved in ovarian tumorigenesis will likely provide new targets for early and effective intervention. Here, we have used serial analysis of gene expression (SAGE) to generate global gene expression profiles from various

Colleen D. Hough; Cheryl A. Sherman-Baust; Ellen S. Pizer; F. J. Montz; Dwight D. Im; Neil B. Rosenshein; Kathleen R. Cho; Gregory J. Riggins; Patrice J. Morin

2000-01-01

261

Gene Expression Profiling in Human Lung Development: An Abundant Resource for Lung Adenocarcinoma Prognosis  

PubMed Central

A tumor can be viewed as a special “organ” that undergoes aberrant and poorly regulated organogenesis. Progress in cancer prognosis and therapy might be facilitated by re-examining distinctive processes that operate during normal development, to elucidate the intrinsic features of cancer that are significantly obscured by its heterogeneity. The global gene expression signatures of 44 human lung tissues at four development stages from Asian descent and 69 lung adenocarcinoma (ADC) tissue samples from ethnic Chinese patients were profiled using microarrays. All of the genes were classified into 27 distinct groups based on their expression patterns (named as PTN1 to PTN27) during the developmental process. In lung ADC, genes whose expression levels decreased steadily during lung development (genes in PTN1) generally had their expression reactivated, while those with uniformly increasing expression levels (genes in PTN27) had their expression suppressed. The genes in PTN1 contain many n-gene signatures that are of prognostic value for lung ADC. The prognostic relevance of a 12-gene demonstrator for patient survival was characterized in five cohorts of healthy and ADC patients [ADC_CICAMS (n?=?69, p?=?0.007), ADC_PNAS (n?=?125, p?=?0.0063), ADC_GSE13213 (n?=?117, p?=?0.0027), ADC_GSE8894 (n?=?62, p?=?0.01), and ADC_NCI (n?=?282, p?=?0.045)] and in four groups of stage I patients [ADC_CICAMS (n?=?22, p?=?0.017), ADC_PNAS (n?=?76, p?=?0.018), ADC_GSE13213 (n?=?79, p?=?0.02), and ADC_qPCR (n?=?62, p?=?0.006)]. In conclusion, by comparison of gene expression profiles during human lung developmental process and lung ADC progression, we revealed that the genes with a uniformly decreasing expression pattern during lung development are of enormous prognostic value for lung ADC. PMID:25141350

Zhang, Yi; Wu, Bo; Di, Xuebing; Jiang, Wei; An, Ning; Lu, Dan; Gao, Suhong; Zhao, Yuda; Chen, Zhaoli; Mao, Yousheng; Gao, Yanning; Zhou, Deshan; Jen, Jin; Liu, Xiaohong; Zhang, Yunping; Li, Xia; Zhang, Kaitai; He, Jie; Cheng, Shujun

2014-01-01

262

Human AZU-1 gene, variants thereof and expressed gene products  

DOEpatents

A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

Chen, Huei-Mei; Bissell, Mina

2004-06-22

263

CHST11 gene expression and DNA methylation in breast cancer  

PubMed Central

Our previously published data link P-selectin-reactive chondroitin sulfate structures on the surface of breast cancer cells to metastatic behavior of cells. We have shown that a particular sulfation pattern mediated by the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggressiveness of human breast cancer cell lines. The present study was performed to evaluate the prognostic value of CHST11 expression and determine whether aberrant DNA methylation controls CHST11 expression in breast cancer. Publicly available datasets were used to examine the association of CHST11 expression to aggressiveness and progression of breast cancer. Methylation status was analyzed using bisulfite genomic sequencing. 5-aza-2?-deoxycytidine (5AzadC) was used for DNA demethylation. Reduced representation bisulfite sequencing was performed in the CpG island of CHST11 with a minimum coverage of 10. Quantitative real-time RT-PCR was employed to confirm the expression profile of CHST11 in breast cancer cell lines. Flow cytometry was also used to confirm the expression of the CHST11 product, chondroitin sulfate A (CS-A). The expression of CHST11 was significantly higher in basal-like and Her2-amplified cell lines compared to luminal cell lines. CHST11 was also highly expressed in cancer tissues compared to normal tissues and the expression levels were significantly associated with tumor progression. We observed very low levels of DNA methylation in a CpG island of CHST11 in basal-like cells but very high levels in the same region in luminal cells. Treatment of MCF7 cells, a luminal cell line with very low expression of CHST11, with 5AzadC increased the expression of CHST11 and its immediate product, CS-A, in a dose-dependent manner. These results suggest that CHST11 may play a direct role in progression of breast cancer and that its expression is controlled by DNA methylation. Therefore, in addition to CHST11 mRNA levels, the methylation status of this gene also has potential as a prognostic biomarker. PMID:25586191

HERMAN, DAMIR; LEAKEY, TATIANA I.; BEHRENS, ALICE; YAO-BORENGASSER, AIWEI; COONEY, CRAIG A.; JOUSHEGHANY, FARIBA; PHANAVANH, BOUNLEUT; SIEGEL, ERIC R.; SAFAR, A. MAZIN; KOROURIAN, SOHEILA; KIEBER-EMMONS, THOMAS; MONZAVI-KARBASSI, BEHJATOLAH

2015-01-01

264

CHST11 gene expression and DNA methylation in breast cancer.  

PubMed

Our previously published data link P-selectin-reactive chondroitin sulfate structures on the surface of breast cancer cells to metastatic behavior of cells. We have shown that a particular sulfation pattern mediated by the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggressiveness of human breast cancer cell lines. The present study was performed to evaluate the prognostic value of CHST11 expression and determine whether aberrant DNA methylation controls CHST11 expression in breast cancer. Publicly available datasets were used to examine the association of CHST11 expression to aggressiveness and progression of breast cancer. Methylation status was analyzed using bisulfite genomic sequencing. 5-aza-2'-deoxycytidine (5AzadC) was used for DNA demethylation. Reduced representation bisulfite sequencing was performed in the CpG island of CHST11 with a minimum coverage of 10. Quantitative real-time RT-PCR was employed to confirm the expression profile of CHST11 in breast cancer cell lines. Flow cytometry was also used to confirm the expression of the CHST11 product, chondroitin sulfate A (CS-A). The expression of CHST11 was significantly higher in basal-like and Her2-amplified cell lines compared to luminal cell lines. CHST11 was also highly expressed in cancer tissues compared to normal tissues and the expression levels were significantly associated with tumor progression. We observed very low levels of DNA methylation in a CpG island of CHST11 in basal-like cells but very high levels in the same region in luminal cells. Treatment of MCF7 cells, a luminal cell line with very low expression of CHST11, with 5AzadC increased the expression of CHST11 and its immediate product, CS-A, in a dose-dependent manner. These results suggest that CHST11 may play a direct role in progression of breast cancer and that its expression is controlled by DNA methylation. Therefore, in addition to CHST11 mRNA levels, the methylation status of this gene also has potential as a prognostic biomarker. PMID:25586191

Herman, Damir; Leakey, Tatiana I; Behrens, Alice; Yao-Borengasser, Aiwei; Cooney, Craig A; Jousheghany, Fariba; Phanavanh, Bounleut; Siegel, Eric R; Safar, A Mazin; Korourian, Soheila; Kieber-Emmons, Thomas; Monzavi-Karbassi, Behjatolah

2015-03-01

265

Disruption mutations of ADA2b and GCN5 transcriptional adaptor genes dramatically affect Arabidopsis growth, development, and gene expression.  

PubMed

We previously identified Arabidopsis genes homologous with the yeast ADA2 and GCN5 genes that encode components of the ADA and SAGA histone acetyltransferase complexes. In this report, we explore the biological roles of the Arabidopsis ADA2b and GCN5 genes. T-DNA insertion mutations in ADA2b and GCN5 were found to have pleiotropic effects on plant growth and development, including dwarf size, aberrant root development, and short petals and stamens in flowers. Approximately 5% of the 8200 genes assayed by DNA microarray analysis showed changes of expression in the mutants, three-fourths of which were upregulated and only half of which were altered similarly in the two mutant strains. In cold acclimation experiments, C-repeat binding factors (CBFs) were induced in the mutants as in wild-type plants, but subsequent transcription of cold-regulated (COR) genes was reduced in both mutants. Remarkably, nonacclimated ada2b-1 (but not gcn5-1) mutant plants were more freezing tolerant than nonacclimated wild-type plants, suggesting that ADA2b may directly or indirectly repress a freezing tolerance mechanism that does not require the expression of CBF or COR genes. We conclude that the Arabidopsis ADA2b and GCN5 proteins have both similar and distinct functions in plant growth, development, and gene expression and may be components of both a common coactivator complex and separate complexes with distinct biological activities. PMID:12615937

Vlachonasios, Konstantinos E; Thomashow, Michael F; Triezenberg, Steven J

2003-03-01

266

Aberrant Expression of Interleukin-1? and Inflammasome Activation in Human Malignant Gliomas  

PubMed Central

Objective Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression. Methods We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay. Results Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1? mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1?/? did not induce IL-1 protein. Glioblastoma IL-1? processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1? processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity. Conclusions Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling. PMID:25054228

Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C.

2014-01-01

267

Gene expression analysis of flax seed development  

PubMed Central

Background Flax, Linum usitatissimum L., is an important crop whose seed oil and stem fiber have multiple industrial applications. Flax seeds are also well-known for their nutritional attributes, viz., omega-3 fatty acids in the oil and lignans and mucilage from the seed coat. In spite of the importance of this crop, there are few molecular resources that can be utilized toward improving seed traits. Here, we describe flax embryo and seed development and generation of comprehensive genomic resources for the flax seed. Results We describe a large-scale generation and analysis of expressed sequences in various tissues. Collectively, the 13 libraries we have used provide a broad representation of genes active in developing embryos (globular, heart, torpedo, cotyledon and mature stages) seed coats (globular and torpedo stages) and endosperm (pooled globular to torpedo stages) and genes expressed in flowers, etiolated seedlings, leaves, and stem tissue. A total of 261,272 expressed sequence tags (EST) (GenBank accessions LIBEST_026995 to LIBEST_027011) were generated. These EST libraries included transcription factor genes that are typically expressed at low levels, indicating that the depth is adequate for in silico expression analysis. Assembly of the ESTs resulted in 30,640 unigenes and 82% of these could be identified on the basis of homology to known and hypothetical genes from other plants. When compared with fully sequenced plant genomes, the flax unigenes resembled poplar and castor bean more than grape, sorghum, rice or Arabidopsis. Nearly one-fifth of these (5,152) had no homologs in sequences reported for any organism, suggesting that this category represents genes that are likely unique to flax. Digital analyses revealed gene expression dynamics for the biosynthesis of a number of important seed constituents during seed development. Conclusions We have developed a foundational database of expressed sequences and collection of plasmid clones that comprise even low-expressed genes such as those encoding transcription factors. This has allowed us to delineate the spatio-temporal aspects of gene expression underlying the biosynthesis of a number of important seed constituents in flax. Flax belongs to a taxonomic group of diverse plants and the large sequence database will allow for evolutionary studies as well. PMID:21529361

2011-01-01

268

Gene expression pattern Hexokinase I is a Gli2-responsive gene expressed in the embryonic CNS  

Microsoft Academic Search

Little is known about the downstream genes regulated by Gli zinc finger transcription factors, which are targets and mediators of Hedgehog signaling. Specifically, the identity and regulation of genes which mediate Gli2 function in neurogenesis are unclear. We describe here the cloning of frog Hexokinase I (HKI) as a Gli2-responsive gene. We show that HKI expression is induced by Gli2

A. Ruiz

269

Ocular Surface Development and Gene Expression  

PubMed Central

The ocular surface—a continuous epithelial surface with regional specializations including the surface and glandular epithelia of the cornea, conjunctiva, and lacrimal and meibomian glands connected by the overlying tear film—plays a central role in vision. Molecular and cellular events involved in embryonic development, postnatal maturation, and maintenance of the ocular surface are precisely regulated at the level of gene expression by a well-coordinated network of transcription factors. A thorough appreciation of the biological characteristics of the ocular surface in terms of its gene expression profiles and their regulation provides us with a valuable insight into the pathophysiology of various blinding disorders that disrupt the normal development, maturation, and/or maintenance of the ocular surface. This paper summarizes the current status of our knowledge related to the ocular surface development and gene expression and the contribution of different transcription factors to this process. PMID:23533700

Swamynathan, Shivalingappa K.

2013-01-01

270

Polyandry and sex-specific gene expression  

PubMed Central

Polyandry is widespread in nature, and has important evolutionary consequences for the evolution of sexual dimorphism and sexual conflict. Although many of the phenotypic consequences of polyandry have been elucidated, our understanding of the impacts of polyandry and mating systems on the genome is in its infancy. Polyandry can intensify selection on sexual characters and generate more intense sexual conflict. This has consequences for sequence evolution, but also for sex-biased gene expression, which acts as a link between mating systems, sex-specific selection and the evolution of sexual dimorphism. We discuss this and the remarkable confluence of sexual-conflict theory and patterns of gene expression, while also making predictions about transcription patterns, mating systems and sexual conflict. Gene expression is a key link in the genotype–phenotype chain, and although in its early stages, understanding the sexual selection–transcription relationship will provide significant insights into this critical association. PMID:23339238

Mank, Judith E.; Wedell, Nina; Hosken, David J.

2013-01-01

271

Polyandry and sex-specific gene expression.  

PubMed

Polyandry is widespread in nature, and has important evolutionary consequences for the evolution of sexual dimorphism and sexual conflict. Although many of the phenotypic consequences of polyandry have been elucidated, our understanding of the impacts of polyandry and mating systems on the genome is in its infancy. Polyandry can intensify selection on sexual characters and generate more intense sexual conflict. This has consequences for sequence evolution, but also for sex-biased gene expression, which acts as a link between mating systems, sex-specific selection and the evolution of sexual dimorphism. We discuss this and the remarkable confluence of sexual-conflict theory and patterns of gene expression, while also making predictions about transcription patterns, mating systems and sexual conflict. Gene expression is a key link in the genotype-phenotype chain, and although in its early stages, understanding the sexual selection-transcription relationship will provide significant insights into this critical association. PMID:23339238

Mank, Judith E; Wedell, Nina; Hosken, David J

2013-03-01

272

Interstitial collagenase gene expression in colonic neoplasia.  

PubMed Central

Tumor invasion and metastasis are complex phenomena believed to be facilitated by the disruption of collagen and elastin fibers in the extracellular matrix. Interstitial collagenase gene expression was studied in colonic adenocarcinoma and adenoma using in situ hybridization. The data indicated that three cell types within the tumor stroma expressed collagenase transcripts; they were eosinophils, fibroblasts, and vascular endothelium. In all 12 adenocarcinomas, a high to moderate level of expression was seen in 1 to 5% of eosinophils and in occasional fibroblasts, whereas these cell types in non-neoplastic mucosa adjacent to tumor showed no detectable expression. Two adenocarcinomas showed expression in hyperplastic endothelium in vascularized granulation tissue. Two out of three adenomas showed expression in eosinophils and fibroblasts at a reduced level. Tissue inhibitor of metalloproteinase-1 gene expression was, however, negligible in all tissue examined. These results suggest that interstitial collagenase gene activation in the tumor stroma, especially eosinophils, may have an important role in tumor invasion and metastasis. Images Figure 1 Figure 2 Figure 3 PMID:8362969

Gray, S. T.; Yun, K.; Motoori, T.; Kuys, Y. M.

1993-01-01

273

Gene expression: degrade to derepress.  

PubMed

Chromatin immunoprecipitation and sequencing (ChIP-seq) provides a static snap-shot of DNA-associated proteins which fails to reflect the dynamics of the DNA-bound proteome. Now, Catic and co-workers combine ubiquitin ChIP-seq and proteasome inhibitors to map sites of DNA-associated protein degradation on a genome-wide scale. They identify an ubiquitin ligase which targets a transcriptional repressor for destruction by the proteasome, thus activating transcription of specific genes. These findings reveal that the ubiquitin proteasome system actively regulates transcription. PMID:24473147

McShane, Erik; Selbach, Matthias

2014-03-01

274

Gene expression profiles in irradiated cancer cells  

NASA Astrophysics Data System (ADS)

Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.

Minafra, L.; Bravatŕ, V.; Russo, G.; Ripamonti, M.; Gilardi, M. C.

2013-07-01

275

Gene expression profiles in irradiated cancer cells  

SciTech Connect

Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.

Minafra, L.; Bravatŕ, V.; Russo, G.; Ripamonti, M.; Gilardi, M. C. [IBFM CNR - LATO, Cefalů, Segrate (Italy)] [IBFM CNR - LATO, Cefalů, Segrate (Italy)

2013-07-26

276

Gene expression profile of AIDS-related Kaposi's sarcoma  

PubMed Central

Background Kaposi's Sarcoma (KS) is a proliferation of aberrant vascular structures lined by spindle cells, and is caused by a gammaherpes virus (HHV8/KSHV). Its course is aggravated by co-infection with HIV-1, where the timing of infection with HIV-1 and HHV8 is important for the clinical outcome. Methods In order to better understand the pathogenesis of KS, we have analysed tissue from two AIDS-KS lesions, and from normal skin by serial analysis of gene expression (SAGE). Semi-quantitative RT-PCR was then used to validate the results. Results The expression profile of AIDS-related KS (AIDS-KS) reflects an active process in the skin. Transcripts of HHV8 were found to be very low, and HIV-1 mRNA was not detected by SAGE, although it could be found using RT-PCR. Comparing the expression profile of AIDS-KS tissue with publicly available SAGE libraries suggested that AIDS-KS mRNA levels are most similar to those in an artificially mixed library of endothelial cells and leukocytes, in line with the description of KS lesions as containing spindle cells with endothelial characteristics, and an inflammatory infiltrate. At least 64 transcripts were found to be significantly elevated, and 28 were statistically downregulated in AIDS-KS compared to normal skin. Five of the upregulated mRNAs, including Tie 1 and sialoadhesin/CD169, were confirmed by semi-quantitative PCR to be elevated in additional AIDS-KS biopsies. Antibodies to sialoadhesin/CD169, a known marker of activated macrophages, were shown to specifically label tumour macrophages. Conclusion The expression profile of AIDS-KS showed 64 genes to be significantly upregulated, and 28 genes downregulated, compared with normal skin. One of the genes with increased expression was sialoadhesin (CD169). Antibodies to sialoadhesin/CD169 specifically labelled tumour-associated macrophages, suggesting that macrophages present in AIDS-KS lesions belong to a subset of human CD169+ macrophages. PMID:12697073

Cornelissen, Marion; van der Kuyl, Antoinette C; van den Burg, Remco; Zorgdrager, Fokla; van Noesel, Carel JM; Goudsmit, Jaap

2003-01-01

277

Anaerobic gene expression in Staphylococcus aureus.  

PubMed

An investigation of gene expression in Staphylococcus aureus after a switch from aerobic to anaerobic growth was initiated by using the proteomic and transcriptomic approaches. In the absence of external electron acceptors like oxygen or nitrate, an induction of glycolytic enzymes was observed. At the same time the amount of tricarboxylic acid cycle enzymes was very low. NAD is regenerated by mixed acid and butanediol fermentation, as indicated by an elevated synthesis level of fermentation enzymes like lactate dehydrogenases (Ldh1 and Ldh2), alcohol dehydrogenases (AdhE and Adh), alpha-acetolactate decarboxylase (BudA1), acetolactate synthase (BudB), and acetoin reductase (SACOL0111) as well as an accumulation of fermentation products as lactate and acetate. Moreover, the transcription of genes possibly involved in secretion of lactate (SACOL2363) and formate (SACOL0301) was found to be induced. The formation of acetyl-coenzyme A or acetyl-phosphate might be catalyzed by pyruvate formate lyase, whose synthesis was found to be strongly induced as well. Although nitrate was not present, the expression of genes related to nitrate respiration (NarH, NarI, and NarJ) and nitrate reduction (NirD) was found to be upregulated. Of particular interest, oxygen concentration might affect the virulence properties of S. aureus by regulating the expression of some virulence-associated genes such as pls, hly, splC and splD, epiG, and isaB. To date, the mechanism of anaerobic gene expression in S. aureus has not been fully characterized. In addition to srrA the mRNA levels of several other regulatory genes with yet unknown functions (e.g., SACOL0201, SACOL2360, and SACOL2658) were found to be upregulated during anaerobic growth, indicating a role in the regulation of anaerobic gene expression. PMID:17384184

Fuchs, Stephan; Pané-Farré, Jan; Kohler, Christian; Hecker, Michael; Engelmann, Susanne

2007-06-01

278

Gene expression profiling in MDS and AML: potential and future avenues.  

PubMed

Today, the classification systems for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) already incorporate cytogenetic and molecular genetic aberrations in an attempt to better reflect disease biology. However, in many MDS/AML patients no genetic aberrations have been identified yet, and even within some cytogenetically well-defined subclasses there is considerable clinical heterogeneity. Recent advances in genomics technologies such as gene expression profiling (GEP) provide powerful tools to further characterize myeloid malignancies at the molecular level, with the goal to refine the MDS/AML classification system, incorporating as yet unknown molecular genetic and epigenetic pathomechanisms, which are likely reflected by aberrant gene expression patterns. In this study, we provide a comprehensive review on how GEP has contributed to a refined molecular taxonomy of MDS and AML with regard to diagnosis, prediction of clinical outcome, discovery of novel subclasses and identification of novel therapeutic targets and novel drugs. As many challenges remain ahead, we discuss the pitfalls of this technology and its potential including future integrative studies with other genomics technologies, which will continue to improve our understanding of malignant transformation in myeloid malignancies and thereby contribute to individualized risk-adapted treatment strategies for MDS and AML patients. PMID:21445077

Theilgaard-Mönch, K; Boultwood, J; Ferrari, S; Giannopoulos, K; Hernandez-Rivas, J M; Kohlmann, A; Morgan, M; Porse, B; Tagliafico, E; Zwaan, C M; Wainscoat, J; Van den Heuvel-Eibrink, M M; Mills, K; Bullinger, L

2011-06-01

279

[The effect of polymorphism of genes of xenobiotics detoxication on the frequencies of spontaneous and induced chromosome aberrations in human lymphocytes].  

PubMed

Here presented the data on the frequencies of chromosome aberrations in lymphocytes of peripheral blood of 97 volunteers depending on genotypes by genes of xenobiotics detoxication before and after gamma-irradiation with dose of 1 Gy in vitro. The frequencies of aberrations were estimated by analyzing not less than 500-1000 metaphases per person. The data of cytogenetic analysis were compared with the results of PCR-genotyping of loci GSTM1, GSTT1, GSTP1, CYP1A1, CYP2D6, NAT2, and MTHFR. The significant differences by the frequencies of aberrations between "single-locus" genotypes were not found except for GSTM1 locus, for which the enhanced frequency of spontaneous aberrations of chromosome type in "positive" genotypes compared to "zero" ones, i.e., homozygotes by deletion (p = 0.04) was observed. The minimum frequency of spontaneous aberrations of chromosome type was recorded for carriers of double homozygotes by deletion of GSTM1-GSTT1: 0.0006 +/- 0.0003 against 0.0027 +/- 0.0003 for the rest of genotypes (p = 0.016 by the Mann-Witney test). The frequency of gamma-induced chromosome aberrations was correlated with the total amount of minor alleles in loci GSTP1, NAT2, and MTHFR (r = 0.25 at p = 0.0065). PMID:19947517

Sal'nikova, L E; Akaeva, E A; Elisova, T V; Kuznetsova, G I; Kuz'mina, N S; Vesnina, I N; Lapteva, N Sh; Chumachenko, A G; Romanchuk, V A; Rubanovich, A V

2009-01-01

280

A regulatory system for target gene expression.  

PubMed

Temporally-regulated expression of endogenous genes is a desirable goal in stable cell line and transgenic animal systems, as well as in clinical gene therapy. Protocols for introducing genes into stable cell lines and experimental animals are often unsatisfactory due to the constitutive expression of such transgenes. To circumvent this problem we have demonstrated specific and temporally regulable expression of a target gene in vivo effected by a chimeric regulator in response to an orally-administered, non-toxic chemical. This regulatory system utilizes a chimeric regulator GLVP, consisting of a mutated human progesterone receptor ligand binding domain (PRLBD-delta) fused to the yeast GAL4 DNA binding domain (DBD) and the HSV VP16 transcriptional activation domain and whose activity is solely regulable by non-physiological doses of RU486 but not by progesterone or other endogenous progestins. Replacing the activation domain of the chimeric regulator with a transcriptional repression domain results in inducible repression of target gene expression in vitro. Our regulatory system functions in transient and stable transfections as well as in transgenic animals, and will have a wide variety of potential applications. PMID:9478886

Burcin, M M; O'Malley, B W; Tsai, S Y

1998-01-01

281

Aberrant expression of sLex and sLea as candidate prognostic factors for feline mammary gland tumour.  

PubMed

Expression of the carbohydrate antigens sialyl Lewis x (sLe(x)) and a (sLe(a)) was evaluated in feline mammary gland tumours (FMGT). Immunohistochemical analysis of tissues from 21 FMGT patients and 11 healthy cats revealed significantly higher sLe(x) and sLe(a) antigen expression in adenocarcinoma tissues compared with that of normal mammary tissues (P <0.01). Serum concentration of sLe(x) was evaluated using an enzyme-linked immunosorbent assay and was significantly higher in the 11 FMGT patients (4.71 ± 10.1 U/ml) than the 22 patients with other disease (2.69 ± 1.59 U/ml) (P = 0.03) and the 22 healthy cats (3.71 ± 1.10 U/ml), although the latter difference was not significant. Although the number of cases examined in this study was small, our findings suggest that aberrant expression of sLe antigens may be induced by tumourigenesis in FMGT and that sLe antigens are potential prognostic tumour markers for FMGT. PMID:24043722

Yoshida, Saori; Yoshida, Kota; Jaroensong, Tassanee; Lee, Soo-Jung; Kamida, Ayako; Saeki, Kohei; Fujita, Naoki; Nishimura, Ryohei; Sasaki, Nobuo; Nakagawa, Takayuki

2014-04-01

282

Clustering of High Throughput Gene Expression Data  

PubMed Central

High throughput biological data need to be processed, analyzed, and interpreted to address problems in life sciences. Bioinformatics, computational biology, and systems biology deal with biological problems using computational methods. Clustering is one of the methods used to gain insight into biological processes, particularly at the genomics level. Clearly, clustering can be used in many areas of biological data analysis. However, this paper presents a review of the current clustering algorithms designed especially for analyzing gene expression data. It is also intended to introduce one of the main problems in bioinformatics - clustering gene expression data - to the operations research community. PMID:23144527

Pirim, Harun; Ek?io?lu, Burak; Perkins, Andy; Yüceer, Çetin

2012-01-01

283

Novel oligoamine analogues inhibit lysine-specific demethylase 1 (LSD1) and induce re-expression of epigenetically silenced genes  

PubMed Central

Purpose Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically-controlled process. Lysine-specific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono- and dimethyl-lysine 4 of histone 3, key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the re-expression of aberrantly silenced genes. Experimental Design Human colorectal cancer cells were treated with the oligoamines and changes in mono- and dimethyl-lysine 4 of histone 3 (H3K4) and other chromatin marks were monitored. In addition, treated cells were evaluated for the re-expression of the aberrantly silenced secreted frizzled-related proteins (SFRPs) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model. Results Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and re-expression of silenced SFRP genes. This re-expression is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, co-treatment with low doses of oligoamines and a DNA methyltransferase (DNMT) inhibitor highly induces the re-expression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo. Conclusions The use of LSD1-inhibiting oligoamine analogues in combination with DNMT inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer. PMID:19934284

Huang, Yi; Stewart, Tracy Murray; Wu, Yu; Baylin, Stephen B.; Marton, Laurence J.; Perkins, Brandy; Jones, Richard J.; Woster, Patrick M.; Casero, Robert A.

2009-01-01

284

Chromatin modifications remodel cardiac gene expression.  

PubMed

Signalling and transcriptional control involve precise programmes of gene activation and suppression necessary for cardiovascular physiology. Deep sequencing of DNA-bound transcription factors reveals a remarkable complexity of co-activators or co-repressors that serve to alter chromatin modification and regulate gene expression. The regulated complexes characterized by genome-wide mapping implicate the recruitment and exchange of proteins with specific enzymatic activities that include roles for histone acetylation and methylation in key developmental programmes of the heart. As for transcriptional changes in response to pathological stress, co-regulatory complexes are also differentially utilized to regulate genes in cardiac disease. Members of the histone deacetylase (HDAC) family catalyse the removal of acetyl groups from proteins whose pharmacological inhibition has profound effects preventing heart failure. HDACs interact with a complex co-regulatory network of transcription factors, chromatin-remodelling complexes, and specific histone modifiers to regulate gene expression in the heart. For example, the histone methyltransferase (HMT), enhancer of zeste homolog 2 (Ezh2), is regulated by HDAC inhibition and associated with pathological cardiac hypertrophy. The challenge now is to target the activity of enzymes involved in protein modification to prevent or reverse the expression of genes implicated with cardiac hypertrophy. In this review, we discuss the role of HDACs and HMTs with a focus on chromatin modification and gene function as well as the clinical treatment of heart failure. PMID:24812277

Mathiyalagan, Prabhu; Keating, Samuel T; Du, Xiao-Jun; El-Osta, Assam

2014-07-01

285

Relationship of eukaryotic DNA replication to committed gene expression: general theory for gene control.  

PubMed Central

The historic arguments for the participation of eukaryotic DNA replication in the control of gene expression are reconsidered along with more recent evidence. An earlier view in which gene commitment was achieved with stable chromatin structures which required DNA replication to reset expression potential (D. D. Brown, Cell 37:359-365, 1984) is further considered. The participation of nonspecific stable repressor of gene activity (histones and other chromatin proteins), as previously proposed, is reexamined. The possible function of positive trans-acting factors is now further developed by considering evidence from DNA virus models. It is proposed that these positive factors act to control the initiation of replicon-specific DNA synthesis in the S phase (early or late replication timing). Stable chromatin assembles during replication into potentially active (early S) or inactive (late S) states with prevailing trans-acting factors (early) or repressing factors (late) and may asymmetrically commit daughter templates. This suggests logical schemes for programming differentiation based on replicons and trans-acting initiators. This proposal requires that DNA replication precede major changes in gene commitment. Prior evidence against a role for DNA replication during terminal differentiation is reexamined along with other results from terminal differentiation of lower eukaryotes. This leads to a proposal that DNA replication may yet underlie terminal gene commitment, but that for it to do so there must exist two distinct modes of replication control. In one mode (mitotic replication) replicon initiation is tightly linked to the cell cycle, whereas the other mode (terminal replication) initiation is not cell cycle restricted, is replicon specific, and can lead to a terminally differentiated state. Aberrant control of mitotic and terminal modes of DNA replication may underlie the transformed state. Implications of a replicon basis for chromatin structure-function and the evolution of metazoan organisms are considered. Images PMID:1943999

Villarreal, L P

1991-01-01

286

Foamy Virus Transactivation and Gene Expression  

Microsoft Academic Search

\\u000a An overview of the pattern and mechanisms of spuma or foamy virus (FV) gene expression is presented. FVs are complex retroviruses\\u000a with respect to their genetic outfit and the elements used to control and regulate expression of the viral genome. The increased\\u000a insight into transcriptional and posttranscriptional mechanisms has revealed that the FVs are distinct, unconventional retroviruses\\u000a clearly apart from

M. Löchelt

287

Promoter methylation and expression levels of selected hematopoietic genes in pediatric B-cell acute lymphoblastic leukemia  

PubMed Central

Background Precursor B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common neoplasm in children and is characterized by genetic and epigenetic aberrations in hematopoietic transcription factor (TF) genes. This study evaluated promoter DNA methylation and aberrant expression levels of early- and late-acting hematopoietic TF genes homeobox A4 and A5 (HOXA4 and HOXA5), Meis homeobox 1 (MEIS1), T-cell acute lymphocytic leukemia 1 (TAL1), and interferon regulatory factors 4 and 8 (IRF4 and IRF8) in pediatric B-cell ALL. Methods Blood samples of 38 ALL patients and 20 controls were obtained. DNA was treated with sodium bisulfite and DNA methylation level of HOXA4, HOXA5, MEIS1, TAL1, IRF4, and IRF8 was assessed using quantitative methylation-specific polymerase chain reaction (PCR). Relative gene expression was measured using quantitative reverse transcription-PCR. Results Aberrant methylation of TAL1, IRF8, MEIS1, and IRF4 was observed in 26.3%, 7.9%, 5.3%, and 2.6% patients, respectively, but not in controls. HOXA4 and HOXA5 were methylated in some controls and hypermethylated in 16% and 5% patients, respectively. IRF8, MEIS1, and TAL1 expression was lower in patients than in controls. MEIS1 expression was inversely correlated with white blood cell (WBC) count. HOXA4 expression was down-regulated in patients with high risk according to the National Cancer Institute (NCI) classification. TAL1 methylation was slightly elevated in patients aged >9 years and in patients showing relapse, suggesting its potential prognostic value. Conclusion Aberrant methylation and expression of the selected hematopoietic genes were correlated with demographic/clinical prognostic factors of pediatric ALL, such as age, WBC count, and NCI risk classification.

Bujko, Mateusz; Kober, Paulina; Wypych, Agnieszka; Gawle-Krawczyk, Karolina; Matysiak, Michal; Siedlecki, Janusz Aleksander

2015-01-01

288

Copy number gain of MYCN gene is a recurrent genetic aberration and favorable prognostic factor in Chinese pediatric neuroblastoma patients  

PubMed Central

Background Amplification of MYCN oncogene is an established marker indicating aggressive tumor progression of neuroblastoma (NBL). But copy number analyses of MYCN gene in ganglioneuroblastoma (GNBL) and ganglioneuroma(GN) is poorly described in the literature. In the study, we evaluated the copy number aberrations of MYCN gene in clinical samples of NBLs, GNBLs and GNs and analyzed their association with clinical outcome of the patients. Methods In this study, we analyzed MYCN gene and chromosome 2 aneusomy by using fluorescence in situ hybridization (FISH) method in a total of 220 patients with NBL, GNBL and GN cases. Kaplan-Meier curves were generated by using SPSS 12.0 software. Results Of 220 patients, 178 (81.0%) were NBLs, 32 (14.5%) were GNBLs and 10 (4.5%) were GNs. MYCN gain is a recurrent genetic aberration of neuroblastic tumors (71.8%, 158/220), which was found in 129 NBLs (58.6%, 129/220), 25 GNBLs (11.4%, 25/220) and 4 GN cases (1.8%, 4/220). However, MYCN amplification was only present in 24 NBL tumors (13.5%, 24/178) and 1 GNBL case (3.1%, 1/32). Kaplan-Meier survival analysis indicated that MYCN amplification is significantly correlated with decreased overall survival in NBLs (P=0.017). Furthermore, a better prognosis trend was observed in patients with MYCN gain tumors compared with those with MYCN gene normal copy number tumors and MYCN amplification tumors (P=0.012). Conclusions In summary, the frequency of MYCN amplification in NBLs is high and is rarely observed in GNBLs and GNs, which suggest MYCN plays an important role in neuroblastic tumors differentiation. MYCN gain appeared to define a subgroup of NBLs with much better outcome and classification of MYCN gene copy number alteration as three groups (amplification, gain and normal) can provide a powerful prognostic indicator in NBLs. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6417541528559124 PMID:23320395

2013-01-01

289

Aberrant EphB/ephrin-B expression in experimental gastric lesions and tumor cells  

PubMed Central

AIM: To determine whether the expression profiles of EphB receptor and ephrin-B ligand can be used as markers for dysplastic/oncogenic transformation in gastric mucosa. METHODS: The protein expression and localization of EphB and ephrin-B in normal, ulcerated regenerating, and dysplastic gastric mucosa were examined in a rat experimental model by immunolabeling, and mRNA expression was assessed in four human gastric carcinoma cell lines by reverse transcription-polymerase chain reaction. RESULTS: Ephrin-B- and EphB-expressing regions were divided along the pit-gland axis in normal gastric units. EphB2 was transiently upregulated in the experimental ulcer, and its expression domain extended to gastric pits and/or the luminal surface where ephrin-B-expressing pit cells reside. EphB2, B3, and B4 and ephrin-B1 were coexpressed in the experimental gastric dysplasia, and more than one ligand-receptor pair was highly expressed in each of the gastric carcinoma cell lines. CONCLUSION: Robust and stable coexpression of EphB and ephrin-B is a feature common to experimentally induced gastric dysplasia and human gastric carcinoma cell lines as compared to normal gastric and ulcerated regenerating epithelia. Thus, EphB/ephrin-B may be a useful marker combination for dysplastic/oncogenic transformation in gastric cancer. PMID:25593460

Uchiyama, Shintaro; Saeki, Noritaka; Ogawa, Kazushige

2015-01-01

290

Aberrant human leucocyte antigen-G expression and its clinical relevance in hepatocellular carcinoma  

PubMed Central

Abstract The clinical relevance of human leucocyte antigen-G (HLA-G) has been postulated in malignancies. Hepatocellular carcinoma (HCC) is a major contributor to cancer incidence and mortality worldwide; however, potential roles of HLA-G in HCC remain unknown. In the current study, HLA-G expression in 219 primary HCC lesions and their adjacent non-tumourous samples was analysed with immunohistochemistry. Correlations among HLA-G expression and various clinical parameters were evaluated. Meanwhile, functional analysis of transfected cell surface HLA-G expression on NK cell cytolysis was performed in vitro. HLA-G expression was observed in 50.2% (110/219) of primary HCC lesions, and undetectable in corresponding adjacent normal liver tissues. HLA-G expression was found in 37.8%, 41.9% and 71.4% of stage I, II and III HCC lesions, respectively. Data revealed that HLA-G expression in HCC was strongly correlated to advanced disease stage (I versus II, P= 0.882; I versus III, P= 0.020; II versus III, P= 0.037). HLA-G expression was also more frequently observed in elder patients (?median 52 years, 57.5%versus 43.4%, P= 0.004). Meanwhile, plasma soluble HLA-G in HCC patients was significantly higher than that in normal controls (median, 92.49U/ml versus 9.29U/ml, P= 0.000). Functional assay showed that HLA-G expression in transfected cells could dramatically decrease the NK cell cytolysis (P= 0.036), which could be markedly restored by the blockade of HLA-G (P= 0.004) and its receptor ILT2 (P= 0.019). Our finding indicated that HLA-G expression was strongly correlated to advanced disease stage, and more frequently observed in elder patients. Its relevance to HCC progression might be result from the inhibition of NK cell cytolysis. PMID:19799650

Lin, A; Chen, H-X; Zhu, C-C; Zhang, X; Xu, H-H; Zhang, J-G; Wang, Q; Zhou, W-J; Yan, W-H

2010-01-01

291

Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy  

PubMed Central

Cancer germline (CG; also known as cancer-testis) antigen genes are normally expressed in germ cells and trophoblast tissues and are aberrantly expressed in a variety of human malignancies. CG antigen genes have high clinical relevance as they encode a class of immunogenic and highly selective tumor antigens. CG antigen-directed immunotherapy is undergoing clinical evaluation for the treatment of a number of solid tumor malignancies and has been demonstrated to be safe, provoke immune responses and be of therapeutic benefit. Achieving an improved understanding of the mechanisms of CG antigen gene regulation will facilitate the continued development of targeted therapeutic approaches against tumors expressing these antigens. Substantial evidence suggests epigenetic mechanisms, particularly DNA methylation, as a primary regulator of CG antigen gene expression in normal and cancer cells as well as in stem cells. The roles of sequence-specific transcription factors and signal transduction pathways in controlling CG antigen gene expression are less clear but are emerging. A combinatorial therapeutic approach involving epigenetic modulatory drugs and CG antigen immunotherapy is suggested based on these data and is being actively pursued. In this article, we review the mechanisms of CG antigen gene regulation and discuss the implications of these mechanisms for the development of cancer immunotherapy approaches targeting CG antigens. PMID:20465387

Akers, Stacey N; Odunsi, Kunle; Karpf, Adam R

2010-01-01

292

Conditional Gene Expression in Mycobacterium abscessus  

PubMed Central

Mycobacterium abscessus is an emerging human pathogen responsible for lung infections, skin and soft-tissue infections and disseminated infections in immunocompromised patients. It may exist either as a smooth (S) or rough (R) morphotype, the latter being associated with increased pathogenicity in various models. Genetic tools for homologous recombination and conditional gene expression are desperately needed to allow the study of M. abscessus virulence. However, descriptions of knock-out (KO) mutants in M. abscessus are rare, with only one KO mutant from an S strain described so far. Moreover, of the three major tools developed for homologous recombination in mycobacteria, only the one based on expression of phage recombinases is working. Several conditional gene expression tools have recently been engineered for Mycobacterium tuberculosis and Mycobacterium smegmatis, but none have been tested yet in M. abscessus. Based on previous experience with genetic tools allowing homologous recombination and their failure in M. abscessus, we evaluated the potential interest of a conditional gene expression approach using a system derived from the two repressors system, TetR/PipOFF. After several steps necessary to adapt TetR/PipOFF for M. abscessus, we have shown the efficiency of this system for conditional expression of an essential mycobacterial gene, fadD32. Inhibition of fadD32 was demonstrated for both the S and R isotypes, with marginally better efficiency for the R isotype. Conditional gene expression using the dedicated TetR/PipOFF system vectors developed here is effective in S and R M. abscessus, and may constitute an interesting approach for future genetic studies in this pathogen. PMID:22195042

Cortes, Mélanie; Singh, Anil Kumar; Gaillard, Jean-Louis; Nassif, Xavier; Herrmann, Jean-Louis

2011-01-01

293

Annotation of gene function in citrus using gene expression information and co-expression networks  

PubMed Central

Background The genus Citrus encompasses major cultivated plants such as sweet orange, mandarin, lemon and grapefruit, among the world’s most economically important fruit crops. With increasing volumes of transcriptomics data available for these species, Gene Co-expression Network (GCN) analysis is a viable option for predicting gene function at a genome-wide scale. GCN analysis is based on a “guilt-by-association” principle whereby genes encoding proteins involved in similar and/or related biological processes may exhibit similar expression patterns across diverse sets of experimental conditions. While bioinformatics resources such as GCN analysis are widely available for efficient gene function prediction in model plant species including Arabidopsis, soybean and rice, in citrus these tools are not yet developed. Results We have constructed a comprehensive GCN for citrus inferred from 297 publicly available Affymetrix Genechip Citrus Genome microarray datasets, providing gene co-expression relationships at a genome-wide scale (33,000 transcripts). The comprehensive citrus GCN consists of a global GCN (condition-independent) and four condition-dependent GCNs that survey the sweet orange species only, all citrus fruit tissues, all citrus leaf tissues, or stress-exposed plants. All of these GCNs are clustered using genome-wide, gene-centric (guide) and graph clustering algorithms for flexibility of gene function prediction. For each putative cluster, gene ontology (GO) enrichment and gene expression specificity analyses were performed to enhance gene function, expression and regulation pattern prediction. The guide-gene approach was used to infer novel roles of genes involved in disease susceptibility and vitamin C metabolism, and graph-clustering approaches were used to investigate isoprenoid/phenylpropanoid metabolism in citrus peel, and citric acid catabolism via the GABA shunt in citrus fruit. Conclusions Integration of citrus gene co-expression networks, functional enrichment analysis and gene expression information provide opportunities to infer gene function in citrus. We present a publicly accessible tool, Network Inference for Citrus Co-Expression (NICCE, http://citrus.adelaide.edu.au/nicce/home.aspx), for the gene co-expression analysis in citrus. PMID:25023870

2014-01-01

294

Ascorbic Acid and Gene Expression: Another Example of Regulation of Gene Expression by Small Molecules?  

PubMed Central

Ascorbic acid (vitamin C, AA) has long been considered a food supplement necessary for life and for preventing scurvy. However, it has been reported that other small molecules such as retinoic acid (vitamin A) and different forms of calciferol (vitamin D) are directly involved in regulating the expression of numerous genes. These molecules bind to receptors that are differentially expressed in the embryo and are therefore crucial signalling molecules in vertebrate development. The question is: is ascorbic acid also a signalling molecule that regulates gene expression? We therefore present and discuss recent publications that demonstrate that AA regulates the expression of a battery of genes. We offer a clue to understanding the biochemical mechanism by which AA regulates gene expression. Finally we will discuss the question of a receptor for AA and its potential involvement in embryonic development and cell differentiation. PMID:20808524

Belin, Sophie; Kaya, Ferdinand; Burtey, Stéphane; Fontes, Michel

2010-01-01

295

Potential translational targets revealed by linking mouse grooming behavioral phenotypes to gene expression using public databases  

PubMed Central

Rodent self-grooming is an important, evolutionarily conserved behavior, highly sensitive to pharmacological and genetic manipulations. Mice with aberrant grooming phenotypes are currently used to model various human disorders. Therefore, it is critical to understand the biology of grooming behavior, and to assess its translational validity to humans. The present in-silico study used publicly available gene expression and behavioral data obtained from several inbred mouse strains in the open-field, light-dark box, elevated plus- and elevated zero-maze tests. As grooming duration differed between strains, our analysis revealed several candidate genes with significant correlations between gene expression in the brain and grooming duration. The Allen Brain Atlas, STRING, GoMiner and Mouse Genome Informatics databases were used to functionally map and analyze these candidate mouse genes against their human orthologs, assessing the strain ranking of their expression and the regional distribution of expression in the mouse brain. This allowed us to identify an interconnected network of candidate genes (which have expression levels that correlate with grooming behavior), display altered patterns of expression in key brain areas related to grooming, and underlie important functions in the brain. Collectively, our results demonstrate the utility of large-scale, high-throughput data-mining and in-silico modeling for linking genomic and behavioral data, as well as their potential to identify novel neural targets for complex neurobehavioral phenotypes, including grooming. PMID:23123364

Roth, Andrew; Kyzar, Evan; Cachat, Jonathan; Stewart, Adam Michael; Green, Jeremy; Gaikwad, Siddharth; O’Leary, Timothy P.; Tabakoff, Boris; Brown, Richard E.; Kalueff, Allan V.

2014-01-01

296

Visualizing Gene Expression In Situ  

SciTech Connect

Visualizing bacterial cells and describing their responses to the environment are difficult tasks. Their small size is the chief reason for the difficulty, which means that we must often use many millions of cells in a sample in order to determine what the average response of the bacteria is. However, an average response can sometimes mask important events in bacterial physiology, which means that our understanding of these organisms will suffer. We have used a variety of instruments to visualize bacterial cells, all of which tell us something different about the sample. We use a fluorescence activated cell sorter to sort cells based on the fluorescence provided by bioreporter genes, and these can be used to select for particular genetic mutations. Cells can be visualized by epifluorescent microscopy, and sensitive photodetectors can be added that allow us to find a single bacterial cell that is fluorescent or bioluminescent. We have also used standard photomultipliers to examine cell aggregates as field bioreporter microorganisms. Examples of each of these instruments show how our understanding of bacterial physiology has changed with the technology.

Burlage, R.S.

1998-11-02

297

Cytogenetic responses to ionizing radiation exposure of human fibroblasts with knocked-down expressions of various DNA damage signaling genes  

NASA Astrophysics Data System (ADS)

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with up-regulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. Here, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yields of MN and/or CA formation were significantly increased by suppressed expression of some of the selected genes in DSB and other DNA repair pathways. Knocked-down expression of other genes showed significant impact on cell cycle progression, possibly because of severe impairment of DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.

Zhang, Ye; Rohde, Larry; Wu, Honglu

298

Gene Trap Insertion Into a Novel Gene Expressed During Mouse Limb Development  

E-print Network

Gene Trap Insertion Into a Novel Gene Expressed During Mouse Limb Development ANDRE´ PIRES¨ttingen, Germany ABSTRACT Gene trapping is a useful method to identify new genes involved in development. Here we describe the spatiotemporal expression of a gene identified in a gene-trap screen. This gene is first

Pires da Silva, Andre

299

The frustrated gene: origins of eukaryotic gene expression  

PubMed Central

Eukarytotic gene expression is frustrated by a series of steps that are generally not observed in prokaryotes and are therefore not essential for the basic chemistry of transcription and translation. Their evolution may have been driven by the need to defend against parasitic nucleic acids. PMID:24209615

Madhani, Hiten D.

2014-01-01

300

Aberrant FGF-2, FGF-3, FGF-4 and C-erb-B2 gene copy number in human ovarian, breast and endometrial tumours.  

PubMed

The important role of oncogene amplification and tumour suppressor gene deletion in human tumours is becoming increasingly apparent. However, extensive screening of human tumours is required before the prognostic significance of such genetic abnormalities can be fully appreciated. The present investigation describes a rapid non-radioactive and largely automated procedure for the analysis of aberrant gene copy number in large numbers of tissue samples of different human tumours. This procedure is based on the sequential use of the polymerase chain reaction (PCR) and high performance ion exchange liquid chromatography (HPIEX). Using this rapid PCR/HPIEX technique, we have identified amplification and deletion of the FGF-2 gene and the FGF-3, FGF-4 and c-erb-B2 oncogenes in human tumours of the breast, ovary and endometrium. Comparison of the data with tumour pathology has revealed possible associations between aberrant gene copy number and tumour type, invasiveness and metastases. PMID:8962718

Schmitt, J F; Susil, B J; Hearn, M T

1996-01-01

301

Imaging gene expression in single living cells  

Microsoft Academic Search

Technical advances in the field of live-cell imaging have introduced the cell biologist to a new, dynamic, subcellular world. The static world of molecules in fixed cells has now been extended to the time dimension. This allows the visualization and quantification of gene expression and intracellular trafficking events of the studied molecules and the associated enzymatic processes in individual cells,

Yaron Shav-Tal; Xavier Darzacq; Robert H. Singer

2004-01-01

302

Gene expression profiling of suicide completers  

Microsoft Academic Search

Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has

L. M. Fiori; G. Turecki

2010-01-01

303

Digital gene expression signatures for maize development  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genome-wide expression signatures detect specific perturbations in developmental programs and contribute to functional resolution of key regulatory networks. In maize (Zea mays) inflorescences, mutations in the RAMOSA (RA) genes affect determinacy of axillary meristems and thus alter branching patt...

304

Functionalization of a protosynaptic gene expression network  

PubMed Central

Assembly of a functioning neuronal synapse requires the precisely coordinated synthesis of many proteins. To understand the evolution of this complex cellular machine, we tracked the developmental expression patterns of a core set of conserved synaptic genes across a representative sampling of the animal kingdom. Coregulation, as measured by correlation of gene expression over development, showed a marked increase as functional nervous systems emerged. In the earliest branching animal phyla (Porifera), in which a nearly complete set of synaptic genes exists in the absence of morphological synapses, these “protosynaptic” genes displayed a lack of global coregulation although small modules of coexpressed genes are readily detectable by using network analysis techniques. These findings suggest that functional synapses evolved by exapting preexisting cellular machines, likely through some modification of regulatory circuitry. Evolutionarily ancient modules continue to operate seamlessly within the synapses of modern animals. This work shows that the application of network techniques to emerging genomic and expression data can provide insights into the evolution of complex cellular machines such as the synapse. PMID:22723359

Conaco, Cecilia; Bassett, Danielle S.; Zhou, Hongjun; Arcila, Mary Luz; Degnan, Sandie M.; Degnan, Bernard M.; Kosik, Kenneth S.

2012-01-01

305

Cluster Analysis of Gene Expression Data  

E-print Network

The expression levels of many thousands of genes can be measured simultaneously by DNA microarrays (chips). This novel experimental tool has revolutionized research in molecular biology and generated considerable excitement. A typical experiment uses a few tens of such chips, each dedicated to a single sample - such as tissue extracted from a particular tumor. The results of such an experiment contain several hundred thousand numbers, that come in the form of a table, of several thousand rows (one for each gene) and 50 - 100 columns (one for each sample). We developed a clustering methodology to mine such data. In this review I provide a very basic introduction to the subject, aimed at a physics audience with no prior knowledge of either gene expression or clustering methods. I explain what genes are, what is gene expression and how it is measured by DNA chips. Next I explain what is meant by "clustering" and how we analyze the massive amounts of data from such experiments, and present results obtained from a...

Domany, E

2002-01-01

306

Promoter methylation confers kidney-specific expression of the Klotho gene  

PubMed Central

The aging suppressor geneKlotho is predominantly expressed in the kidney irrespective of species. Because Klotho protein is an essential component of an endocrine axis that regulates renal phosphate handling, the kidney-specific expression is biologically relevant; however, little is known about its underlying mechanisms. Here we provide in vitro and in vivo evidence indicating that promoter methylation restricts the expression of the Klotho gene in the kidney. Based on evolutionary conservation and histone methylation patterns, the region up to ?1200 bp was defined as a major promoter element of the human Klotho gene. This region displayed promoter activity equally in Klotho-expressing and -nonexpressing cells in transient reporter assays, but the activity was reduced to ?20% when the constructs were integrated into the chromatin in the latter. Both endogenous and transfected Klotho promoters were 30–40% methylated in Klotho-nonexpressing cells, but unmethylated in Klotho-expressing renal tubular cells. DNA demethylating agents increased Klotho expression 1.5- to 3.0-fold in nonexpressing cells and restored the activity of silenced reporter constructs. Finally, we demonstrated that a severe hypomorphic allele of Klotho had aberrant CpG methylation in kl/kl mice. These findings might be useful in therapeutic intervention for accelerated aging and several complications caused by Klotho down-regulation.—Azuma, M., Koyama, D., Kikuchi, J., Yoshizawa, H., Thasinas, D., Shiizaki, K., Kuro-o, M., Furukawa, Y., Kusano, E. Promoter methylation confers kidney-specific expression of the Klotho gene. PMID:22782974

Azuma, Masahiro; Koyama, Daisuke; Kikuchi, Jiro; Yoshizawa, Hiromichi; Thasinas, Dissayabutra; Shiizaki, Kazuhiro; Kuro-o, Makoto; Furukawa, Yusuke; Kusano, Eiji

2012-01-01

307

Fluid Mechanics, Arterial Disease, and Gene Expression  

NASA Astrophysics Data System (ADS)

This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow-induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid mechanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs.

Tarbell, John M.; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong

2014-01-01

308

Fluid Mechanics, Arterial Disease, and Gene Expression  

PubMed Central

This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow–induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial) cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid me chanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs. PMID:25360054

Tarbell, John M.; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong

2014-01-01

309

Fluid Mechanics, Arterial Disease, and Gene Expression.  

PubMed

This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow-induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial) cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid me chanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs. PMID:25360054

Tarbell, John M; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong

2014-01-01

310

Computational Model of the Modulation of Gene Expression Following DNA Damage  

NASA Technical Reports Server (NTRS)

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

Cucinotta, F. A.; Dicello, J. F.; Nikjoo, H.; Cherubini, R.

2002-01-01

311

CpG methylation recruits sequence specific transcription factors essential for tissue specific gene expression  

PubMed Central

CG methylation is an epigenetically inherited chemical modification of DNA found in plants and animals. In mammals it is essential for accurate regulation of gene expression and normal development. Mammalian genomes are depleted for the CG dinucleotide, a result of the chemical deamination of methyl-cytosine in CG resulting in TpG. Most CG dinucleotides are methylated, but ~ 15% are unmethylated. Five percent of CGs cluster into ~20,000 regions termed CG islands (CGI) which are generally unmethylated. About half of CGIs are associated with housekeeping genes. In contrast, the gene body, repeats and transposable elements in which CGs are generally methylated. Unraveling the epigenetic machinery operating in normal cells is important for understanding the epigenetic aberrations that are involved in human diseases including cancer. With the advent of high-throughput sequencing technologies, it is possible to identify the CG methylation status of all 30 million unique CGs in the human genome, and monitor differences in distinct cell types during differentiation and development. Here we summarize the present understanding of DNA methylation in normal cells and discuss resent observations that CG methylation can have an effect on tissue specific gene expression. We also discuss how aberrant CG methylation can lead to cancer. PMID:22387149

Chatterjee, Raghunath; Vinson, Charles

2012-01-01

312

Nitrile-inducible gene expression in mycobacteria  

PubMed Central

summary The ability to ectopically control gene expression is a fundamental tool for the study of bacterial physiology and pathogenesis. While many efficient inducible expression systems are available for Gram-negative bacteria, few are useful in phylogenetically distant organisms, such as mycobacteria. We have adapted a highly-inducible regulon of Rhodococcus rhodochrous to artificially regulate gene expression in both rapidly-growing environmental mycobacteria and slow-growing pathogens, such as Mycobacterium tuberculosis. We demonstrate that this artificial regulatory circuit behaves as a bistable switch, which can be manipulated regardless of growth phase in vitro, and during intracellular growth in macrophages. High-level overexpression is also possible, facilitating biochemical and structural studies of mycobacterial proteins produced in their native host. PMID:18801704

Pandey, Amit K.; Raman, Sahadevan; Proff, Rose; Joshi, Swati; Kang, Choong-Min; Rubin, Eric J.; Husson, Robert N.; Sassetti, Christopher M.

2010-01-01

313

Aberrant Expression of NF-?B in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy  

PubMed Central

Background Up-regulation and association of nuclear factor kappa B (NF-?B) with carcinogenesis and tumor progression has been reported in several malignancies. In the current study, expression of NF-?B in cholangiocarcinoma (CCA) patient tissues and its clinical significance were determined. The possibility of using NF-?B as the therapeutic target of CCA was demonstrated. Methodology Expression of NF-?B in CCA patient tissues was determined using immunohistochemistry. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific NF-?B inhibitor, was used to inhibit NF-?B action. Cell growth was determined using an MTT assay, and cell apoptosis was shown by DNA fragmentation, flow cytometry and immunocytofluorescent staining. Effects of DHMEQ on growth and apoptosis were demonstrated in CCA cell lines and CCA-inoculated mice. DHMEQ-induced apoptosis in patient tissues using a histoculture drug response assay was quantified by TUNEL assay. Principal Findings Normal bile duct epithelia rarely expressed NF-?B (subunits p50, p52 and p65), whereas all CCA patient tissues (n ?=? 48) over-expressed all NF-?B subunits. Inhibiting NF-?B action by DHMEQ significantly inhibited growth of human CCA cell lines in a dose- and time-dependent manner. DHMEQ increased cell apoptosis by decreasing the anti-apoptotic protein expressions–Bcl-2, XIAP–and activating caspase pathway. DHMEQ effectively reduced tumor size in CCA-inoculated mice and induced cell apoptosis in primary histocultures of CCA patient tissues. Conclusions NF-?B was over-expressed in CCA tissues. Inhibition of NF-?B action significantly reduced cell growth and enhanced cell apoptosis. This study highlights NF-?B as a molecular target for CCA therapy. PMID:25170898

Seubwai, Wunchana; Wongkham, Chaisiri; Puapairoj, Anucha; Khuntikeo, Narong; Pugkhem, Ake; Hahnvajanawong, Chariya; Chaiyagool, Jariya; Umezawa, Kazuo; Okada, Seiji; Wongkham, Sopit

2014-01-01

314

Correlation between Gene Expression and GO Semantic Similarity  

Microsoft Academic Search

This research analyzes some aspects of the relationship between gene expression, gene function, and gene annotation. Many recent studies are implicitly based on the assumption that gene products that are biologically and functionally related would maintain this similarity both in their expression profiles as well as in their Gene Ontology (GO) annotation. We analyze how accurate this assumption proves to

Jose L. Sevilla; Victor Segura; Adam Podhorski; Elizabeth Guruceaga; Jose M. Mato; Luis A. Martinez-Cruz; Fernando J. Corrales; Angel Rubio

2005-01-01

315

Identifying In-Trans Process Associated Genes in Breast Cancer by Integrated Analysis of Copy Number and Expression Data  

PubMed Central

Genomic copy number alterations are common in cancer. Finding the genes causally implicated in oncogenesis is challenging because the gain or loss of a chromosomal region may affect a few key driver genes and many passengers. Integrative analyses have opened new vistas for addressing this issue. One approach is to identify genes with frequent copy number alterations and corresponding changes in expression. Several methods also analyse effects of transcriptional changes on known pathways. Here, we propose a method that analyses in-cis correlated genes for evidence of in-trans association to biological processes, with no bias towards processes of a particular type or function. The method aims to identify cis-regulated genes for which the expression correlation to other genes provides further evidence of a network-perturbing role in cancer. The proposed unsupervised approach involves a sequence of statistical tests to systematically narrow down the list of relevant genes, based on integrative analysis of copy number and gene expression data. A novel adjustment method handles confounding effects of co-occurring copy number aberrations, potentially a large source of false positives in such studies. Applying the method to whole-genome copy number and expression data from 100 primary breast carcinomas, 6373 genes were identified as commonly aberrant, 578 were highly in-cis correlated, and 56 were in addition associated in-trans to biological processes. Among these in-trans process associated and cis-correlated (iPAC) genes, 28% have previously been reported as breast cancer associated, and 64% as cancer associated. By combining statistical evidence from three separate subanalyses that focus respectively on copy number, gene expression and the combination of the two, the proposed method identifies several known and novel cancer driver candidates. Validation in an independent data set supports the conclusion that the method identifies genes implicated in cancer. PMID:23382830

Liestřl, Knut; Lipson, Doron; Nyberg, Sandra; Naume, Bjřrn; Sahlberg, Kristine Kleivi; Kristensen, Vessela N.; Břrresen-Dale, Anne-Lise; Lingjćrde, Ole Christian; Yakhini, Zohar

2013-01-01

316

Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling  

PubMed Central

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype. PMID:24416132

Addou-Klouche, Lynda; Finetti, Pascal; Saade, Marie-Rose; Manai, Marwa; Carbuccia, Nadine; Bekhouche, Ismahane; Letessier, Anne; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; Spicuglia, Salvatore; de The, Hugues; Viens, Patrice; Bertucci, François; Birnbaum, Daniel; Chaffanet, Max

2014-01-01

317

Altered Expression of Polycomb Group Genes in Glioblastoma Multiforme  

PubMed Central

The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy. PMID:24260522

Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S.; Jain, Alisha; Jandial, Rahul; Chen, Mike

2013-01-01

318

Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis.  

PubMed

Systemic mastocytosis either presents as aggressive neoplasm with short survival time or indolent systemic mastocytosis with normal life expectancy. In both instances, neoplastic mast cells usually harbor the D816V-mutated variant of KIT. Phenotypically, mast cells in systemic mastocytosis usually express CD25. However, no robust marker that discriminates between aggressive and indolent variants of systemic mastocytosis has been identified yet. We here report that CD30, also known as Ki-1 antigen, is expressed in neoplastic mast cells in a majority of patients with advanced systemic mastocytosis (11/13, 85%), whereas in most patients with indolent systemic mastocytosis (12/45, 27%; P<0.001), only a few if any mast cells stained positive for CD30. These results could be confirmed by TissueFAXS analysis in subsets of patients with indolent systemic mastocytosis (n=7) and advanced systemic mastocytosis (n=4; P=0.008). The mast cell leukemia cell line HMC-1, derived from a patient with aggressive systemic mastocytosis also expressed the CD30 protein. In addition, we were able to detect CD30 mRNA in HMC-1 cells as well as in bone marrow biopsy samples in patients with systemic mastocytosis. In contrast, CD30 transcripts could not be detected in bone marrow biopsies in cases of reactive mast cell hyperplasia and in various other myeloid neoplasms. In conclusion, CD30 is preferentially expressed in neoplastic mast cells in advanced mast cell neoplasms. Upregulated expression of CD30 in advanced systemic mastocytosis may thus be employed as a potential marker for grading systemic mastocytosis in hematopathology. PMID:21186345

Sotlar, Karl; Cerny-Reiterer, Sabine; Petat-Dutter, Karina; Hessel, Harald; Berezowska, Sabina; Müllauer, Leonhard; Valent, Peter; Horny, Hans-Peter

2011-04-01

319

Coevolution of gene expression among interacting proteins  

SciTech Connect

Physically interacting proteins or parts of proteins are expected to evolve in a coordinated manner that preserves proper interactions. Such coevolution at the amino acid-sequence level is well documented and has been used to predict interacting proteins, domains, and amino acids. Interacting proteins are also often precisely coexpressed with one another, presumably to maintain proper stoichiometry among interacting components. Here, we show that the expression levels of physically interacting proteins coevolve. We estimate average expression levels of genes from four closely related fungi of the genus Saccharomyces using the codon adaptation index and show that expression levels of interacting proteins exhibit coordinated changes in these different species. We find that this coevolution of expression is a more powerful predictor of physical interaction than is coevolution of amino acid sequence. These results demonstrate previously uncharacterized coevolution of gene expression, adding a different dimension to the study of the coevolution of interacting proteins and underscoring the importance of maintaining coexpression of interacting proteins over evolutionary time. Our results also suggest that expression coevolution can be used for computational prediction of protein protein interactions.

Fraser, Hunter B.; Hirsh, Aaron E.; Wall, Dennis P.; Eisen,Michael B.

2004-03-01

320

Aberrant cerebellar development of transgenic mice expressing dominant-negative thyroid hormone receptor in cerebellar purkinje cells.  

PubMed

To study the role of the thyroid hormone (TH) in cerebellar development, we generated transgenic mice expressing a dominant-negative TH receptor (TR) in cerebellar Purkinje cells. A mutant human TR?1 (G345R), which binds to the TH-response element but cannot bind to T3, was subcloned into exon 4 of the full-length L7/Pcp-2 gene, which is specifically expressed in Purkinje and retinal rod bipolar cells. The transgene was specifically expressed in Purkinje cells in the postnatal cerebellum. Purkinje cell dendrite arborization was significantly delayed in the transgenic mice. Surprisingly, granule cell migration was also significantly delayed. In the primary cerebellar culture, TH-induced Purkinje cell dendrite arborization was also suppressed. In quantitative real-time RT-PCR analysis, the expression levels of several TH-responsive genes were altered. The expression levels of inositol trisphosphate receptor type 1 and retinoic acid receptor-related orphan receptor? mRNAs, which are mainly expressed in Purkinje cells, and brain-derived neurotrophic factor mRNA, which is expressed in both Purkinje and granule cells, were significantly decreased. The expression levels of neurotrophin-3 and hairless mRNAs, which are mainly expressed in granule cells, and myelin basic protein mRNA, which is mainly expressed in oligodendrocytes, were also decreased. The motor coordination of transgenic mice was significantly disrupted. These results indicate that TH action through its binding to TR in Purkinje cells is required for the normal cerebellar development. TH action through TR in Purkinje cells is also important for the development of other subsets of cerebellar cells such as granule cells and oligodendrocytes. PMID:25603044

Yu, Lu; Iwasaki, Toshiharu; Xu, Ming; Lesmana, Ronny; Xiong, Yu; Shimokawa, Noriaki; Chin, William W; Koibuchi, Noriyuki

2015-04-01

321

Aberrant Expression of PHLPP1 and PHLPP2 Correlates with Poor Prognosis in Patients with Hypopharyngeal Squamous Cell Carcinoma  

PubMed Central

The PHLPP (pleckstrin homology [PH] domain leucine rich repeat protein phosphatase) family, which represents a family of novel Ser/Thr protein phosphatases, is composed of 2 members: PHLPP1 and PHLPP2. PHLPPs partake in diverse cellular activities to exhibit their antitumor and metastasis suppressor functions. It is necessary to investigate the expression patterns of PHLPP1 and PHLPP2 in hypopharyngeal squamous cell carcinomas (HSCCs) and clarify their clinical significance. A total of 138 patients with primary HSCC who underwent curative surgical treatment as an initial treatment were enrolled in this study. A total of 138 HSCC specimens and 64 adjacent noncancerous mucosal epithelial tissues were collected. The expression levels of PHLPP1 and PHLPP2 were examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry assays. Correlations between clinicopathological parameters of the patients were further evaluated. PHLPP1 and PHLPP2 mRNA transcript levels were significantly lower in tumor samples than in paired adjacent nontumor mucosae (P<0.0001, both). Positive correlations were observed between the mRNA levels of PHLPP1 and PHLPP2 in HSCC tissues (correlation coefficient r = 0.678, P<0.001) and in adjacent nontumor mucosae (r = 0.460, P<0.001). The majority of the noncancerous tissues showed high expression levels of PHLPP1 (87.5%, 56/64) and PHLPP2 (85.9%, 55/64). However, the expressions of PHLPP1 and PHLPP2 were significantly decreased in 83.3% (115/138) and 82.6% (114/138) of tumor tissues, respectively (P<0.0001, both). The expressions of both PHLPP isoforms were significantly related to the tumor clinical stage, differentiation, and cervical lymph node metastasis (P<0.05, all). It was PHLPP1 but not PHLPP2 that was significantly related to the tumor T stage. Low PHLPP1 and PHLPP2 expressions were associated with poor overall survival (OS) in HSCC patients (P = 0.004, P = 0.008, respectively). Multivariate analysis revealed that PHLPP1 was an independent prognostic factor for OS. This study indicates that, in HSCC, aberrant expressions of PHLPP1 and PHLPP2 are common events, and loss of PHLPPs might identify patients with poor prognostic outcomes. PMID:25793736

Zhou, Jieyu; Yu, Xuemin; Wang, Juan; Li, Tao; Jin, Tong; Lei, Dapeng; Pan, Xinliang

2015-01-01

322

IRES-Dependent Second Gene Expression Is Significantly Lower Than Cap-Dependent First Gene Expression in a Bicistronic Vector  

Microsoft Academic Search

The internal ribosome entry site (IRES) has been widely used to coexpress heterologous gene products by a message from a single promoter. However, little is known about the efficiency of IRES-dependent second gene expression in comparison with that of first gene expression. This study was undertaken to characterize the relative expression of IRES-dependent second gene in a bicistronic vector, which

Hiroyuki Mizuguchi; Zhili Xu; Akiko Ishii-Watabe; Eriko Uchida; Takao Hayakawa

2000-01-01

323

Inferring Gene Regulatory Networks from Time-Ordered Gene Expression Data Using  

E-print Network

Inferring Gene Regulatory Networks from Time-Ordered Gene Expression Data Using Differential. In time-ordered gene expression data, the expression levels are measured at several points in time genome at the same time. While the amount of available gene expression data has been increasing rapidly

Imoto, Seiya

324

Gene Expression Patterns and Gene Copy Number Changes in Dermatofibrosarcoma Protuberans  

E-print Network

Gene Expression Patterns and Gene Copy Number Changes in Dermatofibrosarcoma Protuberans Sabine C:22), which fuses the COL1A1 and PDGF genes. We determined the characteristic gene expression profile of DFSP cases) and DNA microarray analysis of global gene expression (nine cases). The nine DFSPs were readily

Botstein, David

325

Temporal and spatial expression patterns of canonical clock genes and clock-controlled genes in the  

E-print Network

Temporal and spatial expression patterns of canonical clock genes and clock-controlled genesB)-containing cells is retinorecipient and the cells therein lack rhythmic expression of clock genes and electrical of expression of the canonical clock genes Per1, Per2 and vasopressin mRNA, a clock-controlled gene

Silver, Rae

326

Recombination products suggest the frequent occurrence of aberrant gene replacement in the moss Physcomitrella patens.  

PubMed

In gene replacement, a variant of gene targeting, transformed DNA integrates into the genome by homologous recombination (HR) to replace resident sequences. Gene replacement in the moss Physcomitrella patens is extremely efficient, but often large amounts of additional DNA are integrated at the target locus. A detailed analysis of recombination junctions of PpCOL2 gene knockout mutants shows that the integrated DNA can be highly rearranged. Our data suggest that the replaced sequences were excised by HR and became integrated back into the genome by non-homologous end-joining (NHEJ). RAD51-mediated strand-invasion and subsequent strand-exchange is central to the two-end invasion pathway, the major gene replacement pathway in yeast. In this pathway, integration is initiated by the free ends of a single replacement vector-derived donor molecule which then integrates as an entity. Gene replacement in P. patens is entirely RAD51-dependent suggesting the existence of a pathway mechanistically similar to two-end invasion. However, invasion of the two ends does not seem to be stringently coordinated in P. patens. Actually, often only one fragment end became integrated by HR, or one-sided integration of two independent donor fragments occurred simultaneously leading to a double-strand break that is subsequently sealed by NHEJ and thus causes the observed rearrangements. PMID:25557140

Wendeler, Edelgard; Zobell, Oliver; Chrost, Bozena; Reiss, Bernd

2015-02-01

327

Aberrant expression of neurotrophic factors in the ventricular progenitor cells of infant congenitally hydrocephalic rats  

Microsoft Academic Search

Objects: This study was conducted to investigate the roles of neurotrophic factors in the development of hydrocephalus in HTX rats. Methods: Expressions of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and fibroblast growth factor (FGF)-1 were\\u000a examined immunohistochemically in the cerebral cortex and ventricular zone of 6-day-old rats with congenital hydrocephalus\\u000a (HTX rats). In the ventricular zone of hydrocephalic rats, potent

Hidefumi Fukumitsu; Makoto Ohmiya; Atsumi Nitta; Shoei Furukawa; Tatsuo Mima; Koreaki Mori

2000-01-01

328

Altered Gene Expression Profiles in the Brain, Kidney, and Lung of Deceased Neonatal Cloned Pigs  

PubMed Central

Abstract Limited studies have been published analyzing the gene expression patterns of cloned pigs. We compared the expression profiles of brain, kidney, and lung tissues, representing each of the three germ layers, of deceased neonatal cloned pigs with those of age-matched controls using a 13K oligonucleotide microarray. We found 42 (0.7% of total genes analyzed), 178 (2.9%), and 121 (1.9%) genes differentially expressed in the brain, kidney, and lung of clones, respectively, when compared with the corresponding organs from controls (fold change >1.5, p?expression aberrations could potentially cause the following pathological anomalies in clones: diabetic nephropathy in the kidney and dysregulated surfactant homeostasis in the lung. Interestingly, upregulated expression of genes belonging to the MAPK pathway was observed in all three organs. To investigate whether the differences in levels of gene expression were caused by differential DNA methylation, the global DNA methylation level was measured by high-performance liquid chromatography. In controls, global concentration of methylated cytosine was 5.35%, whereas clones had significantly hypomethylated genomic DNA (4.57%). Bisulfite-pyrosequencing analyses of the promoter regions of differentially expressed candidate genes, c-MYC, Period 1 (PER1), Cathepsin L (CTSL), and Follistatin (FS), however, did not show any differences in the degree of DNA methylation between controls and clones. Our findings demonstrate that deceased neonatal cloned pigs have considerable gene expression abnormalities, which may have contributed to the death of the animals. PMID:20726773

Park, Joonghoon; Marjani, Sadie L.; Lai, Liangxue; Samuel, Melissa; Wax, David; Davis, Steven R.; Bruno, Richard S.; Prather, Randall S.; Yang, Xiangzhong

2010-01-01

329

Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast  

PubMed Central

Understanding the patterns and causes of phenotypic divergence is a central goal in evolutionary biology. Much work has shown that mRNA abundance is highly variable between closely related species. However, the extent and mechanisms of post-transcriptional gene regulatory evolution are largely unknown. Here we used ribosome profiling to compare transcript abundance and translation efficiency in two closely related yeast species (S. cerevisiae and S. paradoxus). By comparing translation regulatory divergence to interspecies differences in mRNA sequence features, we show that differences in transcript leaders and codon bias substantially contribute to divergent translation. Globally, we find that translation regulatory divergence often buffers species differences in mRNA abundance, such that ribosome occupancy is more conserved than transcript abundance. We used allele-specific ribosome profiling in interspecies hybrids to compare the relative contributions of cis- and trans-regulatory divergence to species differences in mRNA abundance and translation efficiency. The mode of gene regulatory divergence differs for these processes, as trans-regulatory changes play a greater role in divergent mRNA abundance than in divergent translation efficiency. Strikingly, most genes with aberrant transcript abundance in F1 hybrids (either over- or underexpressed compared to both parent species) did not exhibit aberrant ribosome occupancy. Our results show that interspecies differences in translation contribute substantially to the evolution of gene expression. Compensatory differences in transcript abundance and translation efficiency may increase the robustness of gene regulation. PMID:24318730

McManus, C. Joel; May, Gemma E.; Spealman, Pieter; Shteyman, Alan

2014-01-01

330

Aberrant Expression of Regulatory Cytokine IL-35 and Pattern Recognition Receptor NOD2 in Patients with Allergic Asthma.  

PubMed

We investigated the plasma concentration of the novel regulatory cytokine IL-35 and intracytosolic pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors in granulocytes and explored their potential implication in disease severity monitoring of allergic asthma. The expression of circulating IL-35 and other pro-inflammatory mediators in asthmatic patients or control subjects were evaluated using enzyme-linked immunosorbent assay (ELISA). The intracellular expressions of NOD1 and NOD2 in CCR3+ granulocytes were assessed using flow cytometry. Plasma concentrations of IL-35, IL-17A, basophil activation marker basogranulin, and eosinophilic airway inflammation biomarker periostin were significantly elevated in allergic asthmatic patients compared to non-atopic control subjects (all probability (p) <0.05). Both granulocyte markers exhibited significant and positive correlation with plasma IL-35 concentration in asthmatic patients (all p?Aberrant expression of NOD2 in granulocytes may be contributed to the impaired innate immunity predisposing allergic asthma. IL-35 may serve as a potential surrogate biomarker for disease severity of allergic asthma. PMID:25326182

Wong, Chun Kwok; Leung, Ting Fan; Chu, Ida Miu Ting; Dong, Jie; Lam, Yvonne Yi On; Lam, Christopher Wai Kei

2015-02-01

331

Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling.  

PubMed

Altered gene expression in tumors can be caused by copy number alterations to DNA or mutation affecting coding or regulatory regions of genes. However, epigenetic events may also influence gene expression. Malignant cells can show major disruptions in DNA methylation profiles, which are manifested as aberrant hypermethylation or as hypomethylation of gene promoters, as well as global genomic hypomethylation. In this study we performed integrative whole-genome analysis of DNA copy number, promoter methylation and gene expression using 10 osteosarcomas. We identified significant changes including: hypomethylation, gain, and overexpression of histone cluster 2 genes at chromosome 1q21.1-q21.3; loss of chromosome 8p21.2-p21.3 and underexpression of DOCK5 and TNFRSF10A/D genes; and amplification-related overexpression of RUNX2 at chromosome 6p12.3-p21.1. Amplification and overexpression of RUNX2 could disrupt G2/M cell cycle checkpoints, and downstream osteosarcoma-specific changes, such as failure of bone differentiation and genomic polyploidization. Failure of DOCK5-signaling, together with p53 and TNFRSF10A/D-related cell cycle and death pathways, may play a critical role in abrogating apoptosis. Our analyses show that the RUNX2 interactome may be constitutively activated in osteosarcoma, and that the downstream intracellular pathways are strongly associated with the regulation of osteoblast differentiation and control of cell cycle and apoptosis in osteosarcoma. PMID:19286668

Sadikovic, Bekim; Yoshimoto, Maisa; Chilton-MacNeill, Susan; Thorner, Paul; Squire, Jeremy A; Zielenska, Maria

2009-06-01

332

Gene expression profiles in skeletal muscle after gene electrotransfer  

PubMed Central

Background Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by force generation measurements. DNA electrotransfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 ?s) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic enzymes. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while HV+LV pulses alone showed preservation of cell integrity. No difference in the force generation capacity was observed in the muscles 2 weeks after DNA electrotransfer. Conclusion The small and transient changes found in the gene expression profiles are of great importance, as this demonstrates that DNA electrotransfer is safe with minor effects on the muscle host cells. These findings are essential for introducing the DNA electrotransfer to muscle for clinical use. Indeed the HV+LV pulse combination used has been optimised to ensure highly efficient and safe DNA electrotransfer. PMID:17598924

Hojman, Pernille; Zibert, John R; Gissel, Hanne; Eriksen, Jens; Gehl, Julie

2007-01-01

333

Consensus gene regulatory networks: combining multiple microarray gene expression datasets  

NASA Astrophysics Data System (ADS)

In this paper we present a method for modelling gene regulatory networks by forming a consensus Bayesian network model from multiple microarray gene expression datasets. Our method is based on combining Bayesian network graph topologies and does not require any special pre-processing of the datasets, such as re-normalisation. We evaluate our method on a synthetic regulatory network and part of the yeast heat-shock response regulatory network using publicly available yeast microarray datasets. Results are promising; the consensus networks formed provide a broader view of the potential underlying network, obtaining an increased true positive rate over networks constructed from a single data source.

Peeling, Emma; Tucker, Allan

2007-09-01

334

FLI1 Expression is Correlated with Breast Cancer Cellular Growth, Migration, and Invasion and Altered Gene Expression  

PubMed Central

ETS factors have been shown to be dysregulated in breast cancer. ETS factors control the expression of genes involved in many biological processes, such as cellular proliferation, differentiation, and apoptosis. FLI1 is an ETS protein aberrantly expressed in retrovirus-induced hematological tumors, but limited attention has been directed towards elucidating the role of FLI1 in epithelial-derived cancers. Using data mining, we show that loss of FLI1 expression is associated with shorter survival and more aggressive phenotypes of breast cancer. Gain and loss of function cellular studies indicate the inhibitory effect of FLI1 expression on cellular growth, migration, and invasion. Using Fli1 mutant mice and both a transgenic murine breast cancer model and an orthotopic injection of syngeneic tumor cells indicates that reduced Fli1 contributes to accelerated tumor growth. Global expression analysis and RNA-Seq data from an invasive human breast cancer cell line with over expression of either FLI1 and another ETS gene, PDEF, shows changes in several cellular pathways associated with cancer, such as the cytokine-cytokine receptor interaction and PI3K-Akt signaling pathways. This study demonstrates a novel role for FLI1 in epithelial cells. In addition, these results reveal that FLI1 down-regulation in breast cancer may promote tumor progression. PMID:25379017

Scheiber, Melissa N.; Watson, Patricia M.; Rumboldt, Tihana; Stanley, Connor; Wilson, Robert C.; Findlay, Victoria J.; Anderson, Paul E.; Watson, Dennis K.

2014-01-01

335

Aberrant expression of microRNAs in serum may identify individuals with pancreatic cancer  

PubMed Central

Pancreatic cancer (PC) has the poorest survival rate among all types of human cancer due to the lack of sensitive and non-invasive diagnostic screen methods for PC screening. Our aim was to identify novel serum microRNA (miRNA) biomarkers for the early detection of PC. We used microarray to screen differential expression of miRNAs in two pooled serum samples (6 PC patients and 6 healthy controls). A panel of miRNAs (22 over-expression and 23 decreased) were deregulated in serum of PC patients in comparison to controls. The expressions of 8 selected miRNAs were further evaluated in sera from 49 PC patients and 27 controls using quantitative reverse transcription-polymerase chain reaction. The levels of serum miR-492 and miR-663a were significantly decreased in PC patients compared with controls (P < 0.05). ROC curve analysis showed that serum miR-492 and miR-663a yield an AUC of 0.787 with 75.5% sensitivity and 70.0% specificity and 0.870 with 85.7% sensitivity and 80.0% specificity, respectively, for discriminating between PC patients and healthy controls. In addition, the level of miR-663a was significantly and inversely associated with TNM stage (P = 0.027). These results suggested that serum miR-492 and miR-663a could have strong potential as novel non-invasive biomarkers for the early detection of PC. PMID:25664025

Lin, Mao-Song; Chen, Wei-Chang; Huang, Jun-Xing; Gao, Heng-Jun; Sheng, Hai-Hui

2014-01-01

336

MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder  

PubMed Central

The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma. PMID:23554734

Cheng, Huan; Deng, Zhonglei; Wang, Zengjun; Zhang, Wei; Su, Jiantang

2012-01-01

337

Engineering Genes for Predictable Protein Expression  

PubMed Central

The DNA sequence used to encode a polypeptide can have dramatic effects on its expression. Lack of readily available tools has until recently inhibited meaningful experimental investigation of this phenomenon. Advances in synthetic biology and the application of modern engineering approaches now provide the tools for systematic analysis of the sequence variables affecting heterologous expression of recombinant proteins. We here discuss how these new tools are being applied and how they circumvent the constraints of previous approaches, highlighting some of the surprising and promising results emerging from the developing field of gene engineering. PMID:22425659

Gustafsson, Claes; Minshull, Jeremy; Govindarajan, Sridhar; Ness, Jon; Villalobos, Alan; Welch, Mark

2013-01-01

338

Plant breeding (review) Transformation of Poaceae and gene expression  

E-print Network

Plant breeding (review) Transformation of Poaceae and gene expression in transgenic plants J Fütterer I Potrykus Institute for Plant Sciences, Federal Institute of Technology, ETH Zürich used for transformation and for achieving controlled gene expression in transgenic plants and discusses

Paris-Sud XI, Université de

339

Optogenetics for gene expression in mammalian cells.  

PubMed

Molecular switches that are controlled by chemicals have evolved as central research instruments in mammalian cell biology. However, these tools are limited in terms of their spatiotemporal resolution due to freely diffusing inducers. These limitations have recently been addressed by the development of optogenetic, genetically encoded, and light-responsive tools that can be controlled with the unprecedented spatiotemporal precision of light. In this article, we first provide a brief overview of currently available optogenetic tools that have been designed to control diverse cellular processes. Then, we focus on recent developments in light-controlled gene expression technologies and provide the reader with a guideline for choosing the most suitable gene expression system. PMID:25153239

Müller, Konrad; Naumann, Sebastian; Weber, Wilfried; Zurbriggen, Matias D

2015-02-01

340

Antiviral effects of inhibiting host gene expression.  

PubMed

RNA interference (RNAi) has been used to probe the virus-host interface to understand the requirements for host-gene expression needed for virus replication. The availability of arrayed siRNA libraries has enabled a genome-scale, high-throughput analysis of gene pathways usurped for virus replication. Results from these and related screens have led to the discovery of new host factors that regulate virus replication. While effective delivery continues to limit development of RNAi-based drugs, RNAi-based genome discovery has led to identification of druggable targets. These validated targets enable rational development of novel antiviral drugs, including the rescue and repurposing of existing, approved drugs. Existing drugs with known cytotoxicity and mechanisms of action can potentially be re-targeted to regulate host genes and gene products needed by influenza to replicate. Drug repositioning is more cost-effective, less time-consuming, and more effective for anti-influenza virus drug discovery than traditional methods. In this chapter, a general overview of RNAi screening methods, host-gene discovery, and drug repurposing is examined with emphasis on utilizing RNAi to identify druggable genes that can be targeted for drug development or repurposing. PMID:25007848

Tripp, Ralph A; Mark Tompkins, S

2015-01-01

341

Global Gene Expression in Staphylococcus aureus Biofilms  

PubMed Central

We previously demonstrated that mutation of the staphylococcal accessory regulator (sarA) in a clinical isolate of Staphylococcus aureus (UAMS-1) results in an impaired capacity to form a biofilm in vitro (K. E. Beenken, J. S. Blevins, and M. S. Smeltzer, Infect. Immun. 71:4206-4211, 2003). In this report, we used a murine model of catheter-based biofilm formation to demonstrate that a UAMS-1 sarA mutant also has a reduced capacity to form a biofilm in vivo. Surprisingly, mutation of the UAMS-1 ica locus had little impact on biofilm formation in vitro or in vivo. In an effort to identify additional loci that might be relevant to biofilm formation and/or the adaptive response required for persistence of S. aureus within a biofilm, we isolated total cellular RNA from UAMS-1 harvested from a biofilm grown in a flow cell and compared the transcriptional profile of this RNA to RNA isolated from both exponential- and stationary-phase planktonic cultures. Comparisons were done using a custom-made Affymetrix GeneChip representing the genomic complement of six strains of S. aureus (COL, N315, Mu50, NCTC 8325, EMRSA-16 [strain 252], and MSSA-476). The results confirm that the sessile lifestyle associated with persistence within a biofilm is distinct by comparison to the lifestyles of both the exponential and postexponential phases of planktonic culture. Indeed, we identified 48 genes in which expression was induced at least twofold in biofilms over expression under both planktonic conditions. Similarly, we identified 84 genes in which expression was repressed by a factor of at least 2 compared to expression under both planktonic conditions. A primary theme that emerged from the analysis of these genes is that persistence within a biofilm requires an adaptive response that limits the deleterious effects of the reduced pH associated with anaerobic growth conditions. PMID:15231800

Beenken, Karen E.; Dunman, Paul M.; McAleese, Fionnuala; Macapagal, Daphne; Murphy, Ellen; Projan, Steven J.; Blevins, Jon S.; Smeltzer, Mark S.

2004-01-01

342

Global gene expression in Staphylococcus aureus biofilms.  

PubMed

We previously demonstrated that mutation of the staphylococcal accessory regulator (sarA) in a clinical isolate of Staphylococcus aureus (UAMS-1) results in an impaired capacity to form a biofilm in vitro (K. E. Beenken, J. S. Blevins, and M. S. Smeltzer, Infect. Immun. 71:4206-4211, 2003). In this report, we used a murine model of catheter-based biofilm formation to demonstrate that a UAMS-1 sarA mutant also has a reduced capacity to form a biofilm in vivo. Surprisingly, mutation of the UAMS-1 ica locus had little impact on biofilm formation in vitro or in vivo. In an effort to identify additional loci that might be relevant to biofilm formation and/or the adaptive response required for persistence of S. aureus within a biofilm, we isolated total cellular RNA from UAMS-1 harvested from a biofilm grown in a flow cell and compared the transcriptional profile of this RNA to RNA isolated from both exponential- and stationary-phase planktonic cultures. Comparisons were done using a custom-made Affymetrix GeneChip representing the genomic complement of six strains of S. aureus (COL, N315, Mu50, NCTC 8325, EMRSA-16 [strain 252], and MSSA-476). The results confirm that the sessile lifestyle associated with persistence within a biofilm is distinct by comparison to the lifestyles of both the exponential and postexponential phases of planktonic culture. Indeed, we identified 48 genes in which expression was induced at least twofold in biofilms over expression under both planktonic conditions. Similarly, we identified 84 genes in which expression was repressed by a factor of at least 2 compared to expression under both planktonic conditions. A primary theme that emerged from the analysis of these genes is that persistence within a biofilm requires an adaptive response that limits the deleterious effects of the reduced pH associated with anaerobic growth conditions. PMID:15231800

Beenken, Karen E; Dunman, Paul M; McAleese, Fionnuala; Macapagal, Daphne; Murphy, Ellen; Projan, Steven J; Blevins, Jon S; Smeltzer, Mark S

2004-07-01

343

Glucocorticoid regulation of human eosinophil gene expression  

Microsoft Academic Search

Molecular analysis of steroid-regulated gene expression in freshly isolated human eosinophils is difficult due to the inherent high rate of spontaneous apoptosis and elevated levels of endogenous ribonucleases. To circumvent these limitations, we determined if the human eosinophilic cell line EoL-1 could serve as an in vitro model of glucocorticoid signaling. We found by optimizing growth conditions in low serum-containing

Sanjay Chauhan; Craig H. Leach; Susan Kunz; John W. Bloomb; Roger L. Miesfeld

2003-01-01

344

Amelogenin Gene Expression in Porcine Odontoblasts  

Microsoft Academic Search

Amelogenin is the major organic component in the enamel matrix of developing teeth and plays an important role in enamel biomineralization. Amelogenin has been reported to be a specific secretory product of ameloblasts. In this study, we examined amelogenin gene expression in various cell layers prepared from a porcine permanent tooth germ using reverse transcription-polymerase chain-reaction (RT-PCR). Amelogenin amplification products

S. Oida; T. Nagano; Y. Yamakoshi; H. Ando; M. Yamada; M. Fukae

2002-01-01

345

Chromatin control of HIV?1 gene expression  

Microsoft Academic Search

Upon infection of susceptible cells, the RNA genome of the human immunodeficiency virus type 1 (HIV?1) is reverse transcribed into double-stranded DNA, which can be subsequently integrated into the cellular genome. After integration, the viral long terminal repeat (LTR) promoter is present in a nucleosome-bound conformation and is transcriptionally silent in the absence of stimulation. Activation of HIV-1 gene expression

Giuseppe Marzio; Mauro Giacca

1999-01-01

346

Gene Expression Microarrays in Cancer Research  

Microsoft Academic Search

The advent of microarray technology has enabled scientists to simultaneously investigate the expression of thousands of genes.\\u000a This technology has been widely used in cancer research to better characterize cancer behaviors at mRNA level and to obtain\\u000a new insights into various stages of carcinogenesis. A microarray-based experiment generally involves three major components:\\u000a microarray manufacturing, sample processing, and data analysis, with

Jian Yan; Weikuan Gu

347

GenomeWide Analysis of Genes, Gene Regulation and Gene Expression  

E-print Network

GenomeWide Analysis of Genes, Gene Regulation and Gene Expression Kathryn Brayer1 , Olivia , Christine Stidley4 and Scott Ness1,5 1 Department of Internal Medicine, Section of Molecular Medicine of Molecular Genetics and Microbiology 4 Department of Internal Medicine, Division of Epidemiology 5 UNM

Maccabe, Barney

348

Reduced expression of Autographa californica nucleopolyhedrovirus ORF34, an essential gene, enhances heterologous gene expression  

SciTech Connect

Autographa californica multiple nucleopolyhedrovirus ORF34 is part of a transcriptional unit that includes ORF32, encoding a viral fibroblast growth factor (FGF) and ORF33. We identified ORF34 as a candidate for deletion to improve protein expression in the baculovirus expression system based on enhanced reporter gene expression in an RNAi screen of virus genes. However, ORF34 was shown to be an essential gene. To explore ORF34 function, deletion (KO34) and rescue bacmids were constructed and characterized. Infection did not spread from primary KO34 transfected cells and supernatants from KO34 transfected cells could not infect fresh Sf21 cells whereas the supernatant from the rescue bacmids transfection could recover the infection. In addition, budded viruses were not observed in KO34 transfected cells by electron microscopy, nor were viral proteins detected from the transfection supernatants by western blots. These demonstrate that ORF34 is an essential gene with a possible role in infectious virus production.

Salem, Tamer Z. [Department of Entomology, Michigan State University, East Lansing, MI 48824 (United States) [Department of Entomology, Michigan State University, East Lansing, MI 48824 (United States); Department of Microbial Molecular Biology, AGERI, Agricultural Research Center, Giza 12619 (Egypt); Division of Biomedical Sciences, Zewail University, Zewail City of Science and Technology, Giza 12588 (Egypt); Zhang, Fengrui [Department of Entomology, Michigan State University, East Lansing, MI 48824 (United States)] [Department of Entomology, Michigan State University, East Lansing, MI 48824 (United States); Thiem, Suzanne M., E-mail: smthiem@msu.edu [Department of Entomology, Michigan State University, East Lansing, MI 48824 (United States); Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824 (United States)

2013-01-20

349

Overexpression of the non-canonical Aux/IAA genes causes auxin-related aberrant phenotypes in Arabidopsis.  

PubMed

Degradation of Aux/IAA proteins which are triggered by the ubiquitin ligase complex containing the auxin F-box receptors (AFBs), is thought to be the primary reaction of auxin signaling. Upon auxin perception, AFBs bind domain II of Aux/IAA proteins that is conserved in most of the 29 family members in Arabidopsis. However, IAA20 and IAA30 lack domain II. Furthermore, IAA31, which forms a single clade with IAA20 and IAA30 in Aux/IAA protein family, has a partially conserved domain II, which contains an amino acid substitution that would cause a dominant mutation of Aux/IAA genes. It has been shown that the half-lives of these proteins are much longer than those of the canonical Aux/IAA proteins. We generated overexpression lines (OXs) of IAA20, IAA30 and IAA31 by the use of cauliflower mosaic virus 35S promoter to better understand the molecular function of atypical Aux/IAA proteins in Arabidopsis. OXs of the three genes exhibited similar auxin-related aberrant phenotypes, with IAA20 OX showing the most severe defects: Some of them showed a semi-dwarf phenotype; gravitropic growth orientation was often affected in hypocotyl and root; vasculature of cotyledons was malformed; the primary root stopped growing soon after germination because of collapse of root apical meristem. IAA 20 and IAA30 were early auxin inducible, but IAA31 was not. These results showed that the wild-type genes of the three Aux/IAAs could disturb auxin physiology when ectopically overexpressed. PMID:18298415

Sato, Atsuko; Yamamoto, Kotaro T

2008-06-01

350

Premature lethality, hyperactivity, and aberrant phosphorylation in transgenic mice expressing a constitutively active form of Fyn  

PubMed Central

The kinase Fyn, the microtubule-associated protein tau and the peptide amyloid-? (A?) constitute a toxic triad in Alzheimer's disease (AD). Tau's subcellular localization is mainly regulated by phosphorylation whereas Fyn's localization is dictated by palmitoylation targeting it to the plasma membrane in a reversible manner. We have previously shown that tau is required for Fyn to be targeted to the dendritic spine. We had also shown that a truncated form of tau (?tau) that accumulates in the cell soma is capable of trapping Fyn and preventing it from entering the spine. Here we determined that palmitoylation is required for Fyn's membrane and spine localization. We further evaluated the functional consequences of neuronal over-expression of the constitutively active Y531F mutant form of Fyn (FynCA) in transgenic mice. We found that the FynCA transgenic mice displayed a reduced weight, a massively reduced lifespan and a high level of hyperactivity. The lifespan of the FynCA mice was only slightly extended by crossing them with ?tau transgenic mice, possibly reflecting differences in expression patterns of the transgenes and high levels of transgenic FynCA compared to endogenous Fyn. Analysis of synaptosomes revealed that FynCA accumulated at high levels in the spine, resulting in increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472. Tau was strongly phosphorylated at the AT8 epitope S202/T205 as shown by Western blot and immunohistochemistry indicating that an increased tyrosine kinase activity of Fyn has down-stream consequences for serine/threonine-directed phosphorylation. PMID:24860422

Xia, Di; Götz, Jürgen

2014-01-01

351

Expression of foreign genes in filamentous cyanobacteria  

SciTech Connect

Several advantages make cyanobacteria attractive hosts for biodegradative genes and possibly for other exogenous genes that have practical uses. The authors have obtained expression in Anabaena sp. strain PCC 7120 and Nostoc ellipsosporum of a dechlorination operon, fcbAB, from Arthrobacter globiformis, and have also developed a simple method for qualitative assessment of dechlorination by microorganisms, such as cyanobacteria, whose metabolism is dependent on the presence of chloride in the medium. Transcription of fcbAB under the control of a variety of promoters was monitored by placing luxAB (encoding luciferase) downstream from fcbAB, and by measuring light emission from luciferase. They believe that the system that they have described has value as a means to screen for factors influencing transcription of foreign genes in cyanobacteria.

Kuritz, T.; Wolk, C.P. (Michigan State Univ., East Lansing (United States))

1993-06-01

352

Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation.  

PubMed

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy. PMID:19860666

Katoh, Y; Katoh, M

2009-09-01

353

Cytogenetic Response to Ionizing Radiation Exposure in Human Fibroblasts with Suppressed Expression of Non-DSB Repair Genes  

NASA Technical Reports Server (NTRS)

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in double-strand break (DSB) repair, and its impact on cytogenetic responses has not been well studied. The purpose of this study is to identify new roles of IR inducible genes in radiation-induced chromosome aberrations and micronuclei formation. In the study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by small interfering RNA in human fibroblast cells. Frequencies of micronuclei (MN) formation and chromosome aberrations were measured to determine the efficiency of cytogenetic repair, and the fraction of bi-nucleated cells in the MN analysis was used as a marker for cell cycle progression. In response to gamma radiation, the formation of MN was significantly increased by suppressed expression of five genes: Ku70 (DSB repair pathway), XPA (nucleotide excision repair pathway), RPA1 (mismatch repair pathway), RAD17 and RBBP8 (cell cycle control). Knocked-down expression of four genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Moreover, decreased XPA, p21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Nine of these eleven genes, whose knock-down expression affected cytogenetic repair, were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate IR-induced biological consequences. Furthermore, eight non-DBS repair genes showed involvement in regulating DSB repair, indicating that successful DSB repair requires both DSB repair mechanisms and non-DSB repair systems.

Zhang, Ye; Rohde, Larry H.; Emami, Kamal; Hammond, Dianne; Mehta, Satish K.; Jeevarajan, Antony S.; Pierson, Duane L.; Wu, Honglu

2009-01-01

354

Transcriptional analysis of human survivin gene expression.  

PubMed

The preservation of tissue and organ homoeostasis depends on the regulated expression of genes controlling apoptosis (programmed cell death). In this study, we have investigated the basal transcriptional requirements of the survivin gene, an IAP (inhibitor of apoptosis) prominently up-regulated in cancer. Analysis of the 5' flanking region of the human survivin gene revealed the presence of a TATA-less promoter containing a canonical CpG island of approximately 250 nt, three cell cycle dependent elements, one cell cycle homology region and numerous Sp1 sites. PCR-based analysis of human genomic DNA, digested with methylation-sensitive and -insensitive restriction enzymes, indicated that the CpG island was unmethylated in both normal and neoplastic tissues. Primer extension and S1 nuclease mapping of the human survivin gene identified two main transcription start sites at position -72 and within -57/-61 from the initiating ATG. Transfection of cervical carcinoma HeLa cells with truncated or nested survivin promoter-luciferase constructs revealed the presence of both enhancer and repressor sequences and identified a minimal promoter region within the proximal -230 nt of the human survivin gene. Unbiased mutagenesis analysis of the human survivin promoter revealed that targeting the Sp1 sequences at position -171 and -151 abolished basal transcriptional activity by approximately 63-82%. Electrophoretic mobility-shift assay with DNA oligonucleotides confirmed formation of a DNA-protein complex between the survivin Sp1 sequences and HeLa cell extracts in a reaction abolished by mutagenesis of the survivin Sp1 sites. These findings identify the basal transcriptional requirements of survivin gene expression. PMID:10567210

Li, F; Altieri, D C

1999-12-01

355

Studying the Complex Expression Dependences between Sets of Coexpressed Genes  

PubMed Central

Organisms simplify the orchestration of gene expression by coregulating genes whose products function together in the cell. The use of clustering methods to obtain sets of coexpressed genes from expression arrays is very common; nevertheless there are no appropriate tools to study the expression networks among these sets of coexpressed genes. The aim of the developed tools is to allow studying the complex expression dependences that exist between sets of coexpressed genes. For this purpose, we start detecting the nonlinear expression relationships between pairs of genes, plus the coexpressed genes. Next, we form networks among sets of coexpressed genes that maintain nonlinear expression dependences between all of them. The expression relationship between the sets of coexpressed genes is defined by the expression relationship between the skeletons of these sets, where this skeleton represents the coexpressed genes with a well-defined nonlinear expression relationship with the skeleton of the other sets. As a result, we can study the nonlinear expression relationships between a target gene and other sets of coexpressed genes, or start the study from the skeleton of the sets, to study the complex relationships of activation and deactivation between the sets of coexpressed genes that carry out the different cellular processes present in the expression experiments. PMID:25147825

Huerta, Mario; Barchino, Roberto; Querol, Enrique

2014-01-01

356

A gene expression database for the molecular pharmacology of cancer  

Microsoft Academic Search

We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discov- ery screen by the National Cancer Institute. Using these data, we linked bioinformatics and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very

Uwe Scherf; Douglas T. Ross; Mark Waltham; Lawrence H. Smith; Jae K. Lee; Lorraine Tanabe; Kurt W. Kohn; William C. Reinhold; Timothy G. Myers; Darren T. Andrews; Dominic A. Scudiero; Michael B. Eisen; Edward A. Sausville; Yves Pommier; David Botstein; Patrick O. Brown; John N. Weinstein

2000-01-01

357

The complexity of gene expression dynamics revealed by permutation entropy  

Microsoft Academic Search

BACKGROUND: High complexity is considered a hallmark of living systems. Here we investigate the complexity of temporal gene expression patterns using the concept of Permutation Entropy (PE) first introduced in dynamical systems theory. The analysis of gene expression data has so far focused primarily on the identification of differentially expressed genes, or on the elucidation of pathway and regulatory relationships.

Xiaoliang Sun; Yong Zou; Victoria J. Nikiforova; Jürgen Kurths; Dirk Walther

2010-01-01

358

Variation in gene expression within and among natural populations  

Microsoft Academic Search

Evolution may depend more strongly on variation in gene expression than on differences between variant forms of proteins. Regions of DNA that affect gene expression are highly variable, containing 0.6% polymorphic sites. These naturally occurring polymorphic nucleotides can alter in vivo transcription rates. Thus, one might expect substantial variation in gene expression between individuals. But the natural variation in mRNA

Marjorie F. Oleksiak; Gary A. Churchill; Douglas L. Crawford

2002-01-01

359

Regulation of Gene Expression by a Metabolic Enzyme  

E-print Network

enzymatic pro- teins can directly control gene expression has not been extensively investigated. Butow, bound specific se- quences, or had a direct role in affecting the expression of specific genes. Zheng etRegulation of Gene Expression by a Metabolic Enzyme David A. Hall,1 Heng Zhu,2 * Xiaowei Zhu,3

Gerstein, Mark

360

Gene expression and the evolution of insect polyphenisms  

E-print Network

Gene expression and the evolution of insect polyphenisms Jay D. Evans1 * and Diana E. Wheeler2 between genomes, gene expression and phenotypes. Here we discuss polyphen- isms and molecular genetic that have tracked gene-expression pat- terns during social insect caste determination. BioEs- says 23

Wheeler, Diana E.

361

Gene Expression Studies in Arabidopsis thaliana -a Network Perspective  

E-print Network

GSB PROOF X Gene Expression Studies in Arabidopsis thaliana - a Network Perspective Aswin Sai ABSTRACT Control at the transcriptional level is the most fundamental mode of regulation of gene expression. Such control can be most effectively studied by monitoring expression patterns of genes in a genome wide

Babu, M. Madan

362

Cellular/Molecular Circadian Gene Expression Regulates Pulsatile  

E-print Network

Cellular/Molecular Circadian Gene Expression Regulates Pulsatile Gonadotropin-Releasing Hormone (Gn­7 cells express many known core circadian clock genes, and we demonstrate that oscillations by transient expression of the dominant-negative Clock- 19 gene disrupts normal ultradian patterns of Gn

Mellon, Pamela L.

363

Quantitative analysis of gene expression in a single  

E-print Network

Quantitative analysis of gene expression in a single cell by qPCR Kiyomi Taniguchi, TomoharuDNA library immobilized on beads for measuring the expression of multiple genes in a single cell. We used roles1. There have recently been several attempts to investigate the heterogeneity of gene expression

Cai, Long

364

Ontogeny of Odorant Receptor Gene Expression in Zebrafish, Danio rerio  

E-print Network

of neurons expressing OR genes through a developmental progression from embryo (12 h postfertilization receptors, zebrafish, placode, olfac- tory neuron, gene expression. 01996John Wiley &Sons,Inc. INTRODUCTION;Ben-Arieet al., 1994)down to 100 in catfish (Ngai et al., 1993b). Neurons expressing specific OR genes

Vogt, Richard G.

365

Differential Gene Expression between Sensory Neocortical Areas: Potential Roles  

E-print Network

Differential Gene Expression between Sensory Neocortical Areas: Potential Roles for Ten_m3 and Bcl6 the regions and confirmed by quantitative polymerase chain reaction 95% of the 20 genes tested. Two genes were adulthood. Retrograde tracing showed that Bcl6 is expressed in corticospinal neurons. Ten_m3 was expressed

Kreiman, Gabriel

366

Expression of X-linked genes in deceased neonates and surviving cloned female piglets.  

PubMed

Animal cloning through somatic cell nuclear transfer (NT) is very inefficient, probably due to insufficient reprogramming of the donor nuclei, which in turn would cause the dysregulation of gene expression. X-Chromosome inactivation (XCI) is a multi-step epigenetic process utilized by mammals to achieve dosage compensation in females. Our aim was to determine if any dysregulation of X-linked genes, which would be indicative of unfaithful reprogramming of donor nuclei, was present in cloned pigs. Real time reverse transcription polymerase chain reaction (RT-PCR) was performed to quantify the transcript levels of five X-linked genes, X inactivation-specific transcript (XIST), TSIX (the reverse spelling of XIST), hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1), glucose-6-phosphate dehydrogenase (G6PD), V-raf murine sarcoma 3,611 viral oncogene homolog 1 (ARAF1), and one autosomal gene, alpha-1 type IV collagen (COL4A1) in major organs of neonatal deceased and surviving female cloned pigs as well as their age-matched control pigs from conventional breeding. Aberrant expression level of these genes was prevalent in the neonatal deceased clones, while it was only moderate in cloned pigs that survived after birth. These results suggest a correlation between the viability of the clones and the normality of their gene expression and provide a possible explanation for the death of a large portion of cloned animals around birth. PMID:17474099

Jiang, Le; Lai, Liangxue; Samuel, Melissa; Prather, Randall S; Yang, Xiangzhong; Tian, X Cindy

2008-02-01

367

Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease  

PubMed Central

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time, transcriptomic analysis for distinct regions of the AD brain using RNA-Seq next-generation sequencing technology. Illumina RNA-Seq analysis was used to survey transcriptome profiles from total brain, frontal and temporal lobe of healthy and AD post-mortem tissue. We quantified gene expression levels, splicing isoforms and alternative transcript start sites. Gene Ontology term enrichment analysis revealed an overrepresentation of genes associated with a neuron's cytological structure and synapse function in AD brain samples. Analysis of the temporal lobe with the Cufflinks tool revealed that transcriptional isoforms of the apolipoprotein E gene, APOE-001, -002 and -005, are under the control of different promoters in normal and AD brain tissue. We also observed differing expression levels of APOE-001 and -002 splice variants in the AD temporal lobe. Our results indicate that alternative splicing and promoter usage of the APOE gene in AD brain tissue might reflect the progression of neurodegeneration. PMID:21283692

Twine, Natalie A.; Janitz, Karolina; Wilkins, Marc R.; Janitz, Michal

2011-01-01

368

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.  

PubMed

Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1+ signature (pro-T), HOX11+ (early cortical thymocyte), and TAL1+ (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia. PMID:12086890

Ferrando, Adolfo A; Neuberg, Donna S; Staunton, Jane; Loh, Mignon L; Huard, Christine; Raimondi, Susana C; Behm, Fred G; Pui, Ching Hon; Downing, James R; Gilliland, D Gary; Lander, Eric S; Golub, Todd R; Look, A Thomas

2002-02-01

369

Gene Expression in the Star Mutation of Petunia x Hybrida  

Technology Transfer Automated Retrieval System (TEKTRAN)

Differences in structural gene expression are responsible for a wide range of responses from human cancer to patterned flowers. Gene silencing is one of the ways in which gene expression is controlled. We have developed a model system to study anthocyanin gene silencing using a mutation in Petunia ...

370

Gravity-Induced Gene Expression in Plants.  

NASA Astrophysics Data System (ADS)

Plants sense changes in their orientation towards the vector of gravity and respond with directional growth. Several metabolites in the signal transduction cascade have been identified. However, very little is known about the interaction between these sensing and signal transduction events and even less is known about their role in the differential growth response. Gravity induced changes in transcript abundance have been identified in Arabidopsis whole seedlings and root apices (Moseyko et al. 2002; Kimbrough et al. 2004). Gravity induced transcript abundance changes can be observed within less than 1 min after stimulation (Salinas-Mondragon et al. 2005). Gene expression however requires not only transcription but also translation of the mRNA. Translation can only occur when mRNA is associated with ribosomes, even though not all mRNA associated with ribosomes is actively translated. To approximate translational capacity we quantified whole genome transcript abundances in corn stem pulvini during the first hour after gravity stimulation in total and poly-ribosomal fractions. As in Arabidopsis root apices, transcript abundances of several clusters of genes responded to gravity stimulation. The vast majority of these transcripts were also found to associate with polyribosomes in the same temporal and quantitative pattern. These genes are transcriptionally regulated by gravity stimulation, but do not exhibit translational regulation. However, a small group of genes showed increased transcriptional regulation after gravity stimulation, but no association with polysomes. These transcripts likely are translationally repressed. The mechanism of translational repression for these transcripts is unknown. Based on the hypothesis that the genes essential for gravitropic responses should be expressed in most or all species, we compared the temporal gravity induced expression pattern of all orthologs identified between maize and Arabidopsis. A small group of genes showed high sequence identity as well as a conserved pattern of transcript abundance changes after gravity stimulation between corn pulvinus tissue and Arabidopsis root apices. The functions of these genes in gravitropic responses are currently being analyzed and should give us important information about evolutionary conserved elements in plant gravity signal transduction. (This research was funded by NASA). Kimbrough, J. M., R. Salinas-Mondragon, et al. (2004). "The Fast and Transient Transcriptional Network of Gravity and Mechanical Stimulation in the Arabidopsis Root Apex." Plant Physiol. 136(1): 2790-2805. Moseyko, N., T. Zhu, et al. (2002). "Transcription profiling of the early gravitropic response in Arabidopsis using high-density oligonucleotide probe microarrays." Plant Physiol 130(2): 720-8. Salinas-Mondragon, R., A. Brogan, et al. (2005). "Gravity and light: integrating transcriptional regulation in roots." Gravit Space Biol Bull 18(2): 121-2.

Sederoff, Heike; Heber, Steffen; Howard, Brian; Myburg-Nichols, Henrietta; Hammond, Rebecca; Salinas-Mondragon, Raul; Brown, Christopher S.

371

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1  

PubMed Central

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBP?), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML. PMID:17671232

Wouters, Bas J.; Jordŕ, Meritxell Alberich; Keeshan, Karen; Louwers, Irene; Erpelinck-Verschueren, Claudia A. J.; Tielemans, Dennis; Langerak, Anton W.; He, Yiping; Yashiro-Ohtani, Yumi; Zhang, Pu; Hetherington, Christopher J.; Verhaak, Roel G. W.; Valk, Peter J. M.; Löwenberg, Bob; Tenen, Daniel G.; Pear, Warren S.

2007-01-01

372

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.  

PubMed

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML. PMID:17671232

Wouters, Bas J; Jordŕ, Meritxell Alberich; Keeshan, Karen; Louwers, Irene; Erpelinck-Verschueren, Claudia A J; Tielemans, Dennis; Langerak, Anton W; He, Yiping; Yashiro-Ohtani, Yumi; Zhang, Pu; Hetherington, Christopher J; Verhaak, Roel G W; Valk, Peter J M; Löwenberg, Bob; Tenen, Daniel G; Pear, Warren S; Delwel, Ruud

2007-11-15

373

Using PCR to Target Misconceptions about Gene Expression  

PubMed Central

We present a PCR-based laboratory exercise that can be used with first- or second-year biology students to help overcome common misconceptions about gene expression. Biology students typically do not have a clear understanding of the difference between genes (DNA) and gene expression (mRNA/protein) and often believe that genes exist in an organism or cell only when they are expressed. This laboratory exercise allows students to carry out a PCR-based experiment designed to challenge their misunderstanding of the difference between genes and gene expression. Students first transform E. coli with an inducible GFP gene containing plasmid and observe induced and un-induced colonies. The following exercise creates cognitive dissonance when actual PCR results contradict their initial (incorrect) predictions of the presence of the GFP gene in transformed cells. Field testing of this laboratory exercise resulted in learning gains on both knowledge and application questions on concepts related to genes and gene expression. PMID:23858358

Wright, Leslie K.; Newman, Dina L.

2013-01-01

374

Using PCR to Target Misconceptions about Gene Expression.  

PubMed

We present a PCR-based laboratory exercise that can be used with first- or second-year biology students to help overcome common misconceptions about gene expression. Biology students typically do not have a clear understanding of the difference between genes (DNA) and gene expression (mRNA/protein) and often believe that genes exist in an organism or cell only when they are expressed. This laboratory exercise allows students to carry out a PCR-based experiment designed to challenge their misunderstanding of the difference between genes and gene expression. Students first transform E. coli with an inducible GFP gene containing plasmid and observe induced and un-induced colonies. The following exercise creates cognitive dissonance when actual PCR results contradict their initial (incorrect) predictions of the presence of the GFP gene in transformed cells. Field testing of this laboratory exercise resulted in learning gains on both knowledge and application questions on concepts related to genes and gene expression. PMID:23858358

Wright, Leslie K; Newman, Dina L

2013-01-01

375

IPO8 and FBXL10: New Reference Genes for Gene Expression Studies in Human Adipose Tissue  

Microsoft Academic Search

Housekeeping genes frequently used in gene expression studies are highly regulated in human adipose tissue. To ensure a correct interpretation of results, it is critical to select appropriate reference genes. Subcutaneous (SC) and omental (OM) adipose tissue expression was analyzed from lean and obese subjects using whole genome complementary DNA (cDNA) microarrays to identify stably expressed genes and commercial TaqMan

Carmen Hurtado del Pozo; Rosa M. Calvo; Gregorio Vesperinas-García; Javier Gómez-Ambrosi; Gema Frühbeck; Ramón Corripio-Sánchez; Miguel A. Rubio; Maria-Jesus Obregon; Maria J. Obregon

2010-01-01

376

Identification and validation of suitable endogenous reference genes for gene expression studies in human peripheral blood  

Microsoft Academic Search

BACKGROUND: Gene expression studies require appropriate normalization methods. One such method uses stably expressed reference genes. Since suitable reference genes appear to be unique for each tissue, we have identified an optimal set of the most stably expressed genes in human blood that can be used for normalization. METHODS: Whole-genome Affymetrix Human 2.0 Plus arrays were examined from 526 samples

Boryana S Stamova; Michelle Apperson; Wynn L Walker; Yingfang Tian; Huichun Xu; Peter Adamczy; Xinhua Zhan; Da-Zhi Liu; Bradley P Ander; Isaac H Liao; Jeffrey P Gregg; Renee J Turner; Glen Jickling; Lisa Lit; Frank R Sharp

2009-01-01

377

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes  

E-print Network

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes by Wen-Hsiung Li, January 5, 2011 (sent for review November 5, 2010) A balance between gene expression studied whether the genetic and epigenetic properties of the promoter affect gene expression variability

Zhang, Jianzhi

378

Inferring gene expression dynamics via functional regression analysis  

PubMed Central

Background Temporal gene expression profiles characterize the time-dynamics of expression of specific genes and are increasingly collected in current gene expression experiments. In the analysis of experiments where gene expression is obtained over the life cycle, it is of interest to relate temporal patterns of gene expression associated with different developmental stages to each other to study patterns of long-term developmental gene regulation. We use tools from functional data analysis to study dynamic changes by relating temporal gene expression profiles of different developmental stages to each other. Results We demonstrate that functional regression methodology can pinpoint relationships that exist between temporary gene expression profiles for different life cycle phases and incorporates dimension reduction as needed for these high-dimensional data. By applying these tools, gene expression profiles for pupa and adult phases are found to be strongly related to the profiles of the same genes obtained during the embryo phase. Moreover, one can distinguish between gene groups that exhibit relationships with positive and others with negative associations between later life and embryonal expression profiles. Specifically, we find a positive relationship in expression for muscle development related genes, and a negative relationship for strictly maternal genes for Drosophila, using temporal gene expression profiles. Conclusion Our findings point to specific reactivation patterns of gene expression during the Drosophila life cycle which differ in characteristic ways between various gene groups. Functional regression emerges as a useful tool for relating gene expression patterns from different developmental stages, and avoids the problems with large numbers of parameters and multiple testing that affect alternative approaches. PMID:18226220

Müller, Hans-Georg; Chiou, Jeng-Min; Leng, Xiaoyan

2008-01-01

379

Spatiotemporal control of gene expression using microfluidics.  

PubMed

Accurate spatiotemporal regulation of genetic expression and cell microenvironment are both essential to epithelial morphogenesis during development, wound healing and cancer. In vivo, this is achieved through the interplay between intrinsic cellular properties and extrinsic signals. Amongst these, morphogen gradients induce specific concentration- and time-dependent gene expression changes that influence a target cell's fate. As systems biology attempts to understand the complex mechanisms underlying morphogenesis, the lack of experimental setup to recapitulate morphogen-induced patterning in vitro has become limiting. For this reason, we developed a versatile microfluidic-based platform to control the spatiotemporal delivery of chemical gradients to tissues grown in Petri dishes. Using this setup combined with a synthetic inducible gene expression system, we were able to restrict a target gene's expression within a confluent epithelium to bands of cells as narrow as four cell diameters with a one cell diameter accuracy. Applied to the targeted delivery of growth factor gradients to a confluent epithelium, this method further enabled the localized induction of epithelial-mesenchymal transitions and associated morphogenetic changes. Our approach paves the way for replicating in vitro the morphogen gradients observed in vivo to determine the relative contributions of known intrinsic and extrinsic factors in differential tissue patterning, during development and cancer. It could also be readily used to spatiotemporally control cell differentiation in ES/iPS cell cultures for re-engineering of complex tissues. Finally, the reversibility of the microfluidic chip assembly allows for pre- and post-treatment sample manipulations and extends the range of patternable samples to animal explants. PMID:24531367

Benedetto, Alexandre; Accetta, Giovanni; Fujita, Yasuyuki; Charras, Guillaume

2014-04-01

380

Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.  

PubMed

The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease. PMID:20530675

Kurek, Kyle C; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Suk-Hee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S; Stein, Janet L; Lian, Jane B; Aqeilan, Rami I

2010-07-01

381

Aberrant DNA methylation in malignant melanoma  

PubMed Central

Malignant Melanoma remains one of the most deadly human cancers with no effective cures for metastatic disease. The poor efficacy of current therapy in advanced melanoma highlights the need for better understanding of molecular mechanisms contributing to the disease. Recent work has shown that epigenetic changes, including aberrant DNA methylation, lead to alterations in gene expression and are as important in the development of malignant melanoma as the specific and well characterized genetic events. Reversion of these methylation patterns could thus lead to a more targeted therapy and are currently under clinical investigation. The purpose of this review is to compile recent information on aberrant DNA methylation of melanoma, to highlight key genes and molecular pathways in melanoma development that have found to be epigenetically altered and to provide insight as of how DNA methylation might serve as targeted treatment option as well as a molecular and prognostic marker in malignant melanoma. PMID:20418788

Schinke, Carolina; Mo, Yongkai; Yu, Yiting; Amiri, Kathy; Sosman, Jeff; Greally, John; Verma, Amit

2010-01-01