Stem cells utilize m6A-mediated decay via YTHDF2 to regulate neural differentiation and promote pluripotency
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PROVIDER: PRJNA552911 | ENA |
REPOSITORIES: ENA
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Project description:The m6A methylation pathway has previously been shown to influence pluripotency. YTHDF2 is an RNA binding protein that interacts with m6A-modified RNAs to facilitate their degradation. We sought to identify the cohort of RNAs targeted by YTHDF2 in human induced pluripotent stem cells (iPSC).
2020-03-21 | GSE133898 | GEO
Project description:N6-methyladenosine (m6A) is the most prevalent internal modification present in the mRNA of all higher eukaryotes. Here we present that m6A is selectively recognized by human YTH domain family (YTHDF2) protein to regulate mRNA degradation. By using crosslinking and immunoprecipitation, we have identified over 4000 substrate RNA of YTHDF2 with conserved core motif of G(m6A)C. We further estabilshed the role of YTHDF2 in RNA metabolism by a combination of ribosome profiling, RNA sequencing, m6A level quantification and cell-based imaging: the C-terminal domain of YTHDF2 selectively binds to m6A of mRNA and the N-terminal domain is responsive for localizing mRNA from translatable pool to processing body where mRNA decay occurs. PAR-CLIP and RIP was used to identify YTHDF2 binding sites followed by ribosome profling and RNA seq to assess the consequences of YTHDF2 siRNA knock-down
2013-11-29 | E-GEOD-49339 | biostudies-arrayexpress
Project description:We report the m6A methylation maps of zebrafish embryos during early development, and transcriptome-wide changes occured in ythdf2 LOF mutant embryos. Our study reveals the m6A-dependent RNA decay as a previously unidentified maternal mode mechanism to regulate maternal mRNA clearance during zebrafish MZT, highlighting the critical role of the m6A mRNA methylation in animal development.
2017-02-07 | GSE79213 | GEO
Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to eventually stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.
2020-03-17 | GSE120860 | GEO
Project description:The m6A modification regulates mRNA stability and translation. Here we show that transcriptomic m6A modification is dynamic and the m6A reader protein YTHDF2 promotes mRNA decay during the cell cycle. Depletion of YTHDF2 leads to the delay of mitotic entry due to overaccumulation of WEE1, a negative regulator of CDK1. We demonstrate that WEE1 transcripts contain m6A modification, which promotes their decay through the m6A reader YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on CDK1 activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified CUL1, CUL4A, DDB1, and SKP2 as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m6A modification, which in turn regulates the cell cycle.
2020-01-01 | GSE134700 | GEO
Project description:As the crucial m6A reader, YTHDF2 usually degrades the target mRNAs by recognizing the m6A modified sites, consequently altering m6A levels of each mRNA. In this study, we used m6A MeRIP sequencing to detect the m6A modification alterations in prostate cancer (PCa) cell line after knocking down YTHDF2 and identify how YTHDF2 promote the PCa progression by mediating the mRNA degradation in m6A-dependent way.
2020-11-09 | GSE129408 | GEO
Project description:The mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human acute myeloid leukemias (AML). To study the role of YTHDF2 on mRNA decay rates in leukemia, c-Kit+ cells from foetal livers of Ythdf2fl/fl; Vav-iCre (Ythdf2CKO) and Ythdf2fl/fl (Ythdf2CTL) 14.5 dpc embryos were transduced with Meis1 and Hoxa9 oncogenes and serially re-plated to generate pre-leukemic cells. Medium with 4SU was used for pre-leukemic cells labelling for 12 hours and was later replaced with 4SU-free medium (time 0). Cells were collected immediately after medium change and at 1, 3 and 9 hours for library generation. RNA from Ythdf2CKO (n=3 biological replicates) and Ythdf2CTL (n=3 biological replicates) pre-leukemic cells were used for SLAM-seq library generation.
2019-04-05 | E-MTAB-7784 | biostudies-arrayexpress
Project description:We found that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 null mutants.To explore the underlying molecular mechanism, we performed transcriptomics and well-established m6A-methylome analyses of NSPCs dervied from wild type and Ythdf2-/- embryo brains. RNA-seq data revealed that expressions of genes enriched in neural development pathways were significantly disturbed. The inhibitory genes, like Flrt2, Ptprd, et al. in regulation of JAK-STAT cascade, which contributes to the neuroprotection and neurite outgrowth, showed increased gene expressions and m6A enrichment by m6A-seq. We identified that without the recognizing and binding of Ythdf2, the degradation of neuron differentiation related m6A-modified mRNAs were delayed in Ythdf2-/-, thereby disturbing the proliferation and differentiation of NSPCs. In summary, our findings uncovered that Ythdf2 modulates neural developmental via regulating the clearance of mRNA targets.
2018-01-01 | GSE104867 | GEO
Project description:We investigated the role of O-GlcNAcylation of m6A reader YTHDF2 in HBV-related hepatocarcinogenesis and progression. We found that YTHDF2 O-GlcNAcylation was elevated upon HBV infection through upregulated HBP. OGT-mediated YTHDF2 O-GlcNAcylation at Ser263 enhanced its protein stability, and subsequently changed the gene expression profiles. Mechanistically, we identified YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 mRNAs in an m6A dependent manner by high-throughput profiling of m6A-seq and RIP-seq, thereby promoting HBV-related HCC tumorigenesis. Importantly, our study proposed that targeting OGT-mediated YTHDF2 O-GlcNAcylation may be a novel strategy for potential treatment of HBV-associated liver cancer.
2023-02-15 | GSE200260 | GEO
Project description:Hematopoietic stem cell expansion through suppression of YTHDF2-mediated m6A-marked mRNA decay
| PRJNA422040 | ENA