YTHDC1 Regulates m6A-Dependent TERT mRNA Stability to Modulates Ovarian Cancer Senescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE306807 | GEO | 2025/11/01
REPOSITORIES: GEO
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Project description:All cancer cells must adopt a telomere maintenance mechanism to achieve replicative immortality. Most human cancer cells utilize the enzyme telomerase to maintain telomeres. Alternative splicing of TERT regulates the amount and function of telomerase, however many alternative splicing isoforms of TERT have unknown functions. Single molecule long read RNA/cDNA sequencing of TERT revealed 45 TERT mRNA variants including 13 known and 32 novel variants. Among the variants, TERT Delta 2-4, which lacks exons 2-4 but retains the original open reading frame, was selected for further study. Induced pluripotent stem cells and cancer cells express higher levels of TERT Delta 2-4 compared to primary human bronchial epithelial cells. Overexpression of TERT Delta 2-4 enhanced clonogenicity and resistance to cisplatin- induced apoptosis. Knockdown of endogenous TERT Delta 2-4 in Calu-6 cells reduced clonogenicity and resistance to cisplatin. Our results suggest that TERT Delta 2-4 enhances cancer cells’ resistance to intrinsic apoptosis. RNA sequencing following knockdown of Delta 2-4 TERT indicates that translation is downregulated and that mitochondrial related proteins are upregulated compared to controls. Overall, our data indicate that TERT produces many isoforms that influence the function TERT and the abundance and activity of telomerase.
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Project description:YTHDC1 is one of m6A reader proteins exerting multifaceted effects on determining the fate of m6A RNA within the nucleus.To understand how YTHDC1 contributes to liver cancer progression, we conducted RNA-seq assay in shCtrl and shDC1 HepG2 cells and aimed to identified YTHDC1-responsive genes.
2025-03-25 | E-MTAB-14193 | biostudies-arrayexpress
Project description:X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 to be its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.
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Project description:All cancer cells must adopt a telomere maintenance mechanism to achieve replicative immortality. Most human cancer cells utilize the enzyme telomerase to maintain telomeres. Alternative splicing of TERT regulates the amount and function of telomerase, however many alternative splicing isoforms of TERT have unknown functions. Single molecule long read RNA/cDNA sequencing of TERT revealed 45 TERT mRNA variants including 13 known and 32 novel variants. Among the variants, TERT Delta 2-4, which lacks exons 2-4 but retains the original open reading frame, was selected for further study. Induced pluripotent stem cells and cancer cells express higher levels of TERT Delta 2-4 compared to primary human bronchial epithelial cells. Overexpression of TERT Delta 2-4 enhanced clonogenicity and resistance to cisplatin- induced apoptosis. Knockdown of endogenous TERT Delta 2-4 in Calu-6 cells reduced clonogenicity and resistance to cisplatin. Our results suggest that TERT Delta 2-4 enhances cancer cells’ resistance to intrinsic apoptosis. RNA sequencing following knockdown of Delta 2-4 TERT indicates that translation is downregulated and that mitochondrial related proteins are upregulated compared to controls. Overall, our data indicate that TERT produces many isoforms that influence the function TERT and the abundance and activity of telomerase.
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Project description:Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identified RNA binding proteins and modifiers that participate in mediating the p53 response. Among the top hits, m6A reader YTHDC1 was identified as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites ofTP53and other genes involved in DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency leads to reducedTP53expression, and also retention of introns leading to aberrant protein production of key DNA damage factors. While intron retention is dependent on m6A, YTHDC1 favoursTP53transcriptionalpause-release independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.
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Project description:Health of endothelial cells (EC) is fundamental for function of vital organs. However, it has not been established whether EC senescence underlies the pathophysiology of aging. Here, we report a mouse model of EC senescence. Inactivation of telomerase (TERT) expression sets the stage for aging and predisposes cells to replicative senescence. TERT maintains telomere length and has telomere-independent effects on cell transcriptome and physiology. We generated mice with TERT gene knock-out (KO) specifically in EC. We analyzed EC from adipose tissues (AT) and skeletal muscle cells from Tert-EC-KO and control mice raised on either chow or high-calorie diet (HCD) and subjected them to RNA sequencing (RNAseq). Single cell RNAseq data were also obtained for subcutaneous and visceral AT. Preliminary analysis of data deposited online indicates that TERT KO induces premature cell senescence and dysfunction. Moreover, HCD feeding exacerbates the effect of TERT loss. We conclude that the Tert-EC-KO mice are a useful model to study EC senescence and its effects on aging-associated organ dysfunction.
2023-12-05 | GSE239687 | GEO
Project description:Heat shock induces a cell response leading to profound changes in genome expression. Recently, N6-methyladenosine (m6A) RNA modification has been implicated in this response, but with limited information of its role in the heat-induced reprograming of gene expression. Most of m6A molecular and cellular functions rely on m6A readers and the best characterized m6A readers are members of the YTH-domain-containing protein family present from yeast to humans. To investigate the function of the nuclear m6A reader YTHDC1, we characterized its binding partners.
2023-01-11 | PXD037414 | Pride
Project description:Health of endothelial cells (EC) is fundamental for function of vital organs. There is evidence accumulating that senescence of EC is associated with aging-related diseases. However, it has not been established whether EC senescence underlies the pathophysiology of aging. Here, we report a mouse model of EC senescence. Inactivation of telomerase (TERT) expression sets the stage for aging and predisposes cells to replicative senescence. TERT maintains telomere length and has telomere-independent effects on cell transcriptome and physiology. We generated mice with TERT gene knock-out (KO) specifically in EC. We analyzed EC from adipose tissues (AT) and skeletal muscle cells from Tert-EC-KO and control mice raised on either chow or high-calorie diet (HCD) and subjected them to RNA sequencing (RNAseq). Single cell RNAseq data were also obtained for subcutaneous and visceral AT. Preliminary analysis of data deposited online indicates that TERT KO induces premature cell senescence and dysfunction. Moreover, HCD feeding exacerbates the effect of TERT loss. We conclude that the Tert-EC-KO mice are a useful model to study EC senescence and its effects on aging-associated organ dysfunction.
2023-12-05 | GSE239686 | 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: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