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Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [ActinoD in E14TG2a ES]

ABSTRACT: Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [ActinoD in E14TG2a ES]

PROVIDER: PRJNA1138725 | ENA |

REPOSITORIES: ENA

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Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [PROseq in E14TG2a ES/EB]

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Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [5mC in ES and EB]

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Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [PROseq in E14TG2a ES/EB]

Project description:Marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links m6A, installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m6A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m6A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m6A are both essential for the differentiation of embryonic stems cells to embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m6A. Our findings add a surprising new dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development, most likely among other biological processes.

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Project description:Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB

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Project description:The epigenetic marking of DNA, histones, and RNA is central for regulating gene expression in development and disease. On DNA, well-characterized 5-methylcytosine (5mC) controls the chromatin state. On mRNA, the most prevalent internal mark, N6-methyladenosine (m6A), installed by METTL3-METTL14 methyltransferases, regulates RNA metabolism. Recent evidences link RNA modifications with epigenetics, notably by connecting m6A to histone marks. The crosstalk between m6A and DNA methylation, however, remains poorly understood. Here we reveal a direct mechanistic link between m6A and DNA methylation. Our findings indicate a proximal co-occurrence of m6A and 5mC marks at gene body and this contributes to enhanced gene expression. We show that the m6A writer METTL3 regulates intragenic methylation and gene expression. Mechanistically, we evidence a direct binding of METTL3-METTL14 to the 5mC methyltransferase DNMT1 and reveal that chromatin-tethered METTL14 recruits DNMT1 to chromatin. We demonstrate that gene-body 5mC and mRNA-stability-enhancing effect of coding-sequence m6A contribute to increased gene expression. We further substantiate our findings in embryonic stem cells by showing that METTL3 regulates gene-body methylation and expression of key differentiation markers. Altogether, our work establishes a key layer of gene expression regulation, involving a direct mechanistic crosstalk between DNA methylation and RNA methylation machinery.

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