Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis
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PROVIDER: PRJNA997906 | ENA |
REPOSITORIES: ENA
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Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.
2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress
Project description:We applied YTHDC1-RIP-seq in SKOV3 cells to identify RNAs directly bound to YTHDC1. A total of 9522 potential candidate targets of YTHDC1 were revealed, and 86.39% of them were mRNA
2024-01-01 | GSE238066 | GEO
Project description:The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression. This SuperSeries is composed of the SubSeries listed below.
2021-01-24 | GSE146467 | GEO
Project description:Nuclear m6A Reader YTHDC1 Promotes Muscle Stem Cell Activation/Proliferation by Regulating mRNA Splicing and Nuclear Export
2023-03-20 | GSE210126 | GEO
Project description:Nuclear m6A Reader YTHDC1 Promotes Muscle Stem Cell Activation/Proliferation by Regulating mRNA Splicing and Nuclear Export
2023-03-20 | GSE210125 | GEO
Project description:N6-methyladenosine (m6A) is the most common internal modification in eukaryotic messenger RNAs (mRNAs) and plays essential roles in mammals. The function of this chemical modification is deciphered by m6A-specific binding proteins of the YTH family. Recent studies indicated that m6A methyltransferase METTL3 ('writer') and demethylase FTO ('eraser') play critical roles in cardiovascular diseases. However, function of m6A 'reader' proteins in the heart is still largely unknown. Here, we report that cardiac-specific ablation of Ythdc1 in postnatal heart exhibits progressive dilated cardiomyopathy, heart failure and dramatically increases the incidence of postnatal lethality. Mechanically, the transcript of Titin-the major DCM and heart failure related gene-is decorated by m6A modification and directly recognized by YTHDC1, deficiency of Ythdc1 in heart results in abnormal splicing of TTN and disarray of sarcomeric structures in the cardiomyocytes subsequently. Collectively, we demonstrated that YTHDC1-dependent TTN splicing is crucial for the postnatal heart development and cardiac function, which probably provides a potential target for treating DCM through tuning m6A modification of TTN mRNA.
2022-08-01 | GSE164353 | GEO
Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader.
2014-09-18 | GSE58352 | GEO
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.
2024-05-07 | GSE239331 | GEO
Project description:RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.
2023-03-25 | GSE193155 | 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