Alternative splicing is a developmental switch for hTERT expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE168193 | GEO | 2021/03/04
REPOSITORIES: GEO
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Project description:Exon and expression analysis of HeLa cells after knockdown of SON Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. Our laboratory recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. A genome-wide screen was performed to identify putative human transcription and splicing targets of Son. HeLa cells were transfected with siRNA against SON or a control siRNA (siLuciferase) for 48 hours. Five biological replicates were used for each condition.
2011-12-22 | E-GEOD-28672 | biostudies-arrayexpress
Project description:Exon and expression analysis of HeLa cells after knockdown of SON Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. Our laboratory recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. A genome-wide screen was performed to identify putative human transcription and splicing targets of Son.
2011-12-22 | GSE28672 | GEO
Project description:A gene expression signature classifying telomerase and ALT immortalisation reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT Telomere length is maintained by 2 known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown previously that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation, however other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling we have uncovered a signature of 1305 genes to distinguish telomerase positive and ALT cell lines. By combining this with gene expression profiles of liposarcoma tissue samples we refined this signature to 297 genes significantly associated with telomere maintenance mechanism. Network analysis of known direct interactions between genes within this signature revealed a regulatory signalling network consistent with a model of hTERT repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. In addition we show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalisation in cell lines and mesenchymal tissues. Keywords: cell type comparison, gene expression
2009-11-02 | GSE14487 | GEO
Project description:A gene expression signature classifying telomerase and ALT immortalisation reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT Telomere length is maintained by 2 known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown previously that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation, however other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling we have uncovered a signature of 1305 genes to distinguish telomerase positive and ALT cell lines. By combining this with gene expression profiles of liposarcoma tissue samples we refined this signature to 297 genes significantly associated with telomere maintenance mechanism. Network analysis of known direct interactions between genes within this signature revealed a regulatory signalling network consistent with a model of hTERT repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. In addition we show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalisation in cell lines and mesenchymal tissues. Keywords: cell type comparison, gene expression
2009-11-02 | GSE14529 | GEO
Project description:Human telomerase, hTERT, catalyzes telomere elongation using the hTR long noncoding RNA (lncRNA) template and confers replicative immortality, a hallmark of cancer. hTERT is reactivated in nearly 90% of cancers and telomere elongation was considered its sole role in tumorigenesis. However, evidence for telomere-independent hTERT cell phenotypes, which surprisingly require hTERT catalytic activity, is mounting. These phenotypes could profoundly impact our understanding and clinical exploitation of hTERT’s role in cancer, but their underlying mechanisms remain unclear. One mechanism was suggested by the demonstration of hTERT’s ability to bind an alternative lncRNA, RMRP, and synthesize double-stranded RNAs that are processed into Argonaute2-bound small interfering RNAs that suppress the lncRNA itself. Here we performed systematic lncRNA profiling to determine whether this is a general mode of hTERT action involving novel lncRNAs, and investigated the implications of hTERT-mediated lncRNA suppression for tumorigenesis. We found that hTERT’s telomere-independent catalytic activity increased cell survival resulting in luminal hyperplasia in a human breast acinar morphogenesis model. Using next-generation sequencing of Argonaute2-associated small RNAs, we discovered novel hTERT-downregulated lncRNAs. One such lncRNA, MEG3, could bind hTERT and was significantly downregulated in human breast carcinoma cell lines and tissues. MEG3 knockdown promoted survival and hyperplasia, consistent with early tumorigenesis, and ectopic MEG3 expression caused cell death and inhibited breast cancer cell proliferation. Microarray analysis identified Bcl2-interacting proteins, BEX1 and BNIPL, as MEG3 targets. BEX1 mediates cell death by decreasing phospho-Bcl2, and MEG3 or hTERT modulated phospho-Bcl2 levels. This pathway could, in part, underlie the observed phenotypes. Collectively, our findings show that hTERT can suppress multiple lncRNAs, including MEG3, and establish a novel mechanism of hTERT-mediated proliferative control that could facilitate tumorigenesis. Our mechanistic insights suggest that small RNA-directed diagnostic and therapeutic strategies will be relevant for targeting hTERT.
2016-09-17 | GSE61546 | GEO
Project description:Limitless reproductive potential is one of the hallmarks of cancer cells1. This ability is accomplished by maintaining telomeres, which erosion otherwise causes cellular senescence or death. Human cancer cells often maintain shorter telomeres than do cells in surrounding normal tissues2-5. While most cancer cells activate telomerase, which can elongate telomeres6, it remains elusive why cancer cells keep telomeres short. Here we show that forced elongation of telomeres in cancer cells promotes their differentiation in a tumor microenvironment in vivo. We elongated telomeres of human prostate cancer PC-3 cells, which possess short telomeres7, by enhancing their telomerase activity. The resulting cells with long telomeres retain an ability to form tumors in a mouse xenograft model. Strikingly, these tumors exhibit many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These phenotypic changes are caused by telomere elongation per se but not enhanced telomerase activity. Gene expression profiling revealed that telomere elongation correlates with inhibition of cell-cycle processes. Together, our results suggest a functional contribution of short telomeres to tumor malignancy by regulating cancer cell differentiation. Two samples are telomere-elongated cells, both in the presence and absence of the exogenous hTERT. The other two samples are control cell lines.
2013-05-31 | E-GEOD-36649 | biostudies-arrayexpress
Project description:Limitless reproductive potential is one of the hallmarks of cancer cells1. This ability is accomplished by maintaining telomeres, which erosion otherwise causes cellular senescence or death. Human cancer cells often maintain shorter telomeres than do cells in surrounding normal tissues2-5. While most cancer cells activate telomerase, which can elongate telomeres6, it remains elusive why cancer cells keep telomeres short. Here we show that forced elongation of telomeres in cancer cells promotes their differentiation in a tumor microenvironment in vivo. We elongated telomeres of human prostate cancer PC-3 cells, which possess short telomeres7, by enhancing their telomerase activity. The resulting cells with long telomeres retain an ability to form tumors in a mouse xenograft model. Strikingly, these tumors exhibit many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These phenotypic changes are caused by telomere elongation per se but not enhanced telomerase activity. Gene expression profiling revealed that telomere elongation correlates with inhibition of cell-cycle processes. Together, our results suggest a functional contribution of short telomeres to tumor malignancy by regulating cancer cell differentiation. Two cell lines are telomere-elongated cells, both in the presence and absence of the exogenous hTERT. The other two lines are control PC-3 cell lines. We extracted RNA from four independent xenograft tumors per original cell line.
2013-05-31 | E-GEOD-41559 | biostudies-arrayexpress
Project description:Gene expression profiling was performed by use of serial analysis of gene expression (SAGE) on BJ normal human skin fibroblasts, A-T cells, and BJ and A-T cells transduced with hTERT cDNA and expressing telomerase activity. Keywords = telomere Keywords = telomerase Keywords = TERT Keywords = ataxia telangiectasia mutated Keywords = ATM Keywords = serial analysis of gene expression Keywords = SAGE Keywords = fibroblast Keywords: parallel sample
2004-01-16 | E-GEOD-953 | biostudies-arrayexpress
Project description:We have found that knockdown of the human telomerase RNA template, hTR, induces Bim-mediated apoptosis independent of telomere length in primary human CD4 T cells, whereas knockdown of the telomerase enzymatic protein, hTERT does not induce apoptosis in the timeframe of our studies. We used microarray analysis to determine any gene changes in human primary CD4 T cells that could provide mechanistic insight into hTR knockdown induced apoptosis. Cells with control shScramble, shTERT, and shTR were used in this experiment
2014-08-28 | GSE60855 | GEO
Project description:Telomere elongation by telomerase is critical for the proliferation of human stem cells and >85-90% of cancer cells. The repression of telomerase activity during cellular differentiation promotes replicative aging and function as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain unclear. We found that HoxC5 repressed hTERT, via a previously uncharacterized upstream enhancer element. HoxC5 interacts with co-repressors Pbx4 and Meis3, and recruits Class I histone deacetylases, to mediate repression of hTERT. The upstream enhancer element are conserved in long-lived primates, and HOXC5 are activated upon differentiation, consistent with diminished telomerase activity. Thus, HoxC5/Pbx4/Meis3 together constitute a developmental-controlled regulatory loop that coordinates transcriptional repression of hTERT.
2018-02-13 | GSE97570 | GEO