Chromosomal rearrangements juxtapose the TERT coding sequence to strong enhancer elements
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147181 | GEO | 2021/03/01
REPOSITORIES: GEO
Similar Datasets
Project description:Whole genome sequencing detected structural rearrangements of TERT in 17/75 high stage neuroblastoma with 5 cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted immediate up- and down-stream regions of TERT, placing in 7 cases a super-enhancer close to the breakpoints. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high stage neuroblastoma, each associated with very poor prognosis
2015-10-21 | GSE73537 | GEO
Project description:Chromosomal rearrangements juxtapose the TERT coding sequence to strong enhancer elements
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Project description:Blocking telomerase is recognized as a key anti-cancer mechanism. Unlike in stem cells, levels of telomerase catalytic subunit TERT are limiting in reconstituting telomerase activity in somatic cells. However in some cancers, Tert is transcriptionally reactivated by mutations in its promoter. Given that Tert in stem cells is driven by WT Tert promoter, if we can selectively target Tert reactivation through mutant Tert promoters we can block telomerase activity specifically in cancer cells without toxicity in stem cells. Here we report the epigenetic regulation of Tert promoter comparing WT and mutant promoters. We showed that GABPA homodimerization through long-range interaction stabilizes Gabpa to drive Tert expression. Furthermore, BRD4 specifically activates the C250T mutant promoter via dual mechanism involving GABPA, thereby setting the stage for future therapeutics.
2017-02-27 | GSE77265 | GEO
Project description:Whole genome sequencing detected structural rearrangements of TERT in 17/75 high stage neuroblastoma with 5 cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted immediate up- and down-stream regions of TERT, placing in 7 cases a super-enhancer close to the breakpoints. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high stage neuroblastoma, each associated with very poor prognosis. This submission contains all newly sequenced samples only.
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Project description:Genome wide DNA methylation profiling of high-risk TERT-rearranged neuroblastoma cells treated with solvent or HDAC inhibitor panobinostat. The Illumina HumanMethylation EPIC Beadchip was used to obtain DNA methylation profiles. Samples included 3 solvent treated samples and 3 panobinostat-treated samples after 18 h of treatment.
2022-08-04 | GSE155703 | GEO
Project description:Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line, B16F10, we have previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression. To identify the gene responsible for the regulation of TERT transcription, we performed cDNA microarray analysis using parental B16F10 cells, telomerase negative B16F10 microcell hybrids with a human chromosome 5 (B16F10MH5), and its revertant clones (MH5R) with reactivated telomerase. Here we report the identification of PITX1, whose restoration leads to the downregulation of mouse tert (mtert) transcription, as a TERT suppressor gene. Additionally, both human TERT (hTERT) and mouse TERT (mtert) promoter activity can be suppressed by PITX1. We showed that three and one binding sites, respectively, within the hTERT and mtert promoters that express a unique conserved region are responsible for the transcriptional activation of TERT. Furthermore, we showed that PITX1 binds to the TERT promoter both in vitro and in vivo. Thus, PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity.
2010-09-10 | GSE23216 | GEO
Project description:Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line, B16F10, we have previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression. To identify the gene responsible for the regulation of TERT transcription, we performed cDNA microarray analysis using parental B16F10 cells, telomerase negative B16F10 microcell hybrids with a human chromosome 5 (B16F10MH5), and its revertant clones (MH5R) with reactivated telomerase. Here we report the identification of PITX1, whose restoration leads to the downregulation of mouse tert (mtert) transcription, as a TERT suppressor gene. Additionally, both human TERT (hTERT) and mouse TERT (mtert) promoter activity can be suppressed by PITX1. We showed that three and one binding sites, respectively, within the hTERT and mtert promoters that express a unique conserved region are responsible for the transcriptional activation of TERT. Furthermore, we showed that PITX1 binds to the TERT promoter both in vitro and in vivo. Thus, PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity. We transferred intact human chromosome 5 into mouse melanoma B16F10 cells by microcell fusion. The microcell hybrids (MH5) exhibited suppression of telomerase, we also obtained revertant clones (MH5R) in which telomerase is reactivated. To identify the differentially expressed genes on human chromosome 5, we performed expression microarray analysis using these two clones and parental B16F10 cells.
2010-09-10 | E-GEOD-23216 | biostudies-arrayexpress
Project description:Promoter rearrangement of the telomerase reverse transcriptase (TERT) gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis. TERT associated oncogenic signaling in neuroblastoma remains unclear. Gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients revealed a coordinated activation of oncogenic signaling pathways and differentially overexpressed gene signature in a subgroup of MycN non-amplified neuroblastomas with TERT overexpression. ChIP-seq analysis of human neuroblastoma cell line CLB-GA harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. We demonstrated a critical regulatory role of Brd4 and cyclin-dependent kinases in the expression and chromatin activation. Inhibition of both with AZD5153 and dinaciclib proved most effective in tumor growth suppression of neuroblastoma cell lines, primary cells, and xenograft. Our study provides a therapeutic strategy utilizing epigenetic targeting of neuroblastoma with TERT overexpression.
2020-05-12 | GSE133453 | GEO
Project description:Analysis of TERT-regulated global gene expression changes. The hypothesis tested in the present study was that neuronal TERT influences the regulation of gene expressions. Results provide important information of the response of in vivo mouse neurons to physiological TERT induction.
2021-10-12 | GSE163523 | GEO
Project description:Point mutations within the TERT promoter are the most common recurrent somatic non-coding mutation identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma and bladder cancer. They are most abundant at C146T and C124T and more rare at A57C, with the latter originally described as a familial case but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in the reactivation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the C146T, C124T and A57C mutations. While we confirmed binding of multiple ETS factors to the mutant C146T and C124T sequences, we identified E4F1 a an A57C-specific binder and ZNF148 as a TERT WT binder that is excluded from the TERT promoter by the C124T allele. Both proteins are activating transcription factors that bind specifically to the A57C and wildtype (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity.
2023-11-04 | PXD037776 | Pride