Similar Datasets
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.
2025-01-10 | GSE218291 | GEO
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.
2025-01-10 | GSE218292 | GEO
Project description:Epigenetic marking of the genome via modifications of DNA and histones is central to the regulation of gene expression. DNA methylation is a well-characterized modification involved in regulating chromatin states. RNA also undergoes modifications. The most prevalent internal modification of mRNA is N6-methyladenosine (m6A) installed co-transcriptionally by the METTL3-METTL14 methyltransferases. This process is an essential post-transcriptional mechanism of gene regulation. Recent evidence links m6A function to histone modifications. Here we reveal a direct connection between m6A and DNA methylation. We find that the DNA methyltransferase DNMT1 interacts both in vitro and in vivo with METTL14 within the METTL3-METTL14 complex. Using genome- and transcriptome-wide mapping, we show that methylated cytosine (5mC) tends to occur in DNA near positions corresponding to m6A sites in mRNAs, especially in gene bodies, this being associated with increased gene expression. This tight co-occurrence of 5mC and m6A appears to be favoured by a high m6A density. METTL3-depleted cells display strong intragenic DNA hypomethylation and reduced genome-wide binding of DNMT1 to DNA as evidenced by ChIP-Seq, this leading to reduced expression of the corresponding genes. We provide further mechanistic insights by showing in vitro that m6A impedes binding of DNMT1 to RNA. Accordingly, transcriptome-wide mapping of DNMT1 in vivo confirms that METTL3-mediated m6A formation interferes with DNMT1 binding to mRNA targets, causing increased gene expression. Together, our results reveal that METTL3-METTL14 favors intragenic DNA methylation by causing DNMT1 to be repelled from mRNA by m6A and targeted to gene bodies, thereby promoting transcriptional activation. They highlight a previously unrecognized layer of gene expression regulation, involving a direct mechanistic link between DNA methylation and RNA modification.
2025-01-10 | GSE184754 | GEO
Project description:Epigenetic marking of the genome via modifications of DNA and histones is central to the regulation of gene expression. DNA methylation is a well-characterized modification involved in regulating chromatin states. RNA also undergoes modifications. The most prevalent internal modification of mRNA is N6-methyladenosine (m6A) installed co-transcriptionally by the METTL3-METTL14 methyltransferases. This process is an essential post-transcriptional mechanism of gene regulation. Recent evidence links m6A function to histone modifications. Here we reveal a direct connection between m6A and DNA methylation. We find that the DNA methyltransferase DNMT1 interacts both in vitro and in vivo with METTL14 within the METTL3-METTL14 complex. Using genome- and transcriptome-wide mapping, we show that methylated cytosine (5mC) tends to occur in DNA near positions corresponding to m6A sites in mRNAs, especially in gene bodies, this being associated with increased gene expression. This tight co-occurrence of 5mC and m6A appears to be favoured by a high m6A density. METTL3-depleted cells display strong intragenic DNA hypomethylation and reduced genome-wide binding of DNMT1 to DNA as evidenced by ChIP-Seq, this leading to reduced expression of the corresponding genes. We provide further mechanistic insights by showing in vitro that m6A impedes binding of DNMT1 to RNA. Accordingly, transcriptome-wide mapping of DNMT1 in vivo confirms that METTL3-mediated m6A formation interferes with DNMT1 binding to mRNA targets, causing increased gene expression. Together, our results reveal that METTL3-METTL14 favors intragenic DNA methylation by causing DNMT1 to be repelled from mRNA by m6A and targeted to gene bodies, thereby promoting transcriptional activation. They highlight a previously unrecognized layer of gene expression regulation, involving a direct mechanistic link between DNA methylation and RNA modification.
2025-01-10 | GSE184756 | GEO
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.
2025-01-10 | GSE272783 | GEO
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.
2025-01-10 | GSE272788 | GEO
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.
2025-01-10 | GSE272780 | GEO
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.
2025-01-10 | GSE272782 | GEO
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.
2025-01-10 | GSE272787 | GEO
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.
2025-01-10 | GSE272791 | GEO