H3K36me2 recruits DNMT3A and shapes intergenic DNA methylation landscapes
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ABSTRACT:
PROVIDER: PRJNA486798 | ENA |
REPOSITORIES: ENA
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Project description:Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A lead to a childhood overgrowth syndrome that is phenotypically overlapping with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2), pointing to a potential mechanistic link between the two disorders. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows binding and activity of DNMT3A are co-localized with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in mouse and human cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Consistently, PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by overgrowth syndrome-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that, when perturbed, promotes neoplastic and developmental overgrowth.
2019-08-30 | GSE118785 | GEO
Project description: Not available
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Project description:DNA methylation at the 5-position of cytosine (5mC) is a crucial epigenetic mark in regulating biological processes including gene silencing, gene imprinting, and X chromosome inactivation. It has long been questioned how de novo DNA 5mC patterns are established in different genomic regions and whether histone modifications crosstalk to the process. Here, we report a previously uncovered mechanism of histone mark H3K36me2 in recruiting and activating DNMT3A, primarily in the intergenic regions. Our biochemistry studies discovered that H3K36me2 could be specifically bound by DNMT3A PWWP domain and substantially stimulate DNMT3A activity, representing the first example of histone modification in activating DNMT3A activity. Using multiple myeloma model, KMS11, we further found that the genome-wide gain-of-H3K36me2 resulted in global increase of 5mC, primarily in the intergenic regions. Importantly, DNA inhibitor treatment specifically blocked KMS11 growth demonstrating the functional importance of this regulatory pathway.
2019-12-31 | GSE140304 | GEO
Project description:DNA methylation at the 5-position of cytosine (5mC) is a crucial epigenetic mark in regulating biological processes including gene silencing, gene imprinting, and X chromosome inactivation. It has long been questioned how de novo DNA 5mC patterns are established in different genomic regions and whether histone modifications crosstalk to the process. Here, we report a previously uncovered mechanism of histone mark H3K36me2 in recruiting and activating DNMT3A, primarily in the intergenic regions. Our biochemistry studies discovered that H3K36me2 could be specifically bound by DNMT3A PWWP domain and substantially stimulate DNMT3A activity, representing the first example of histone modification in activating DNMT3A activity. Using multiple myeloma model, KMS11, we further found that the genome-wide gain-of-H3K36me2 resulted in global increase of 5mC, primarily in the intergenic regions. Importantly, DNA inhibitor treatment specifically blocked KMS11 growth demonstrating the functional importance of this regulatory pathway.
2019-12-31 | GSE140303 | GEO
Project description:DNA methylation at the 5-position of cytosine (5mC) is a crucial epigenetic mark in regulating biological processes including gene silencing, gene imprinting, and X chromosome inactivation. It has long been questioned how de novo DNA 5mC patterns are established in different genomic regions and whether histone modifications crosstalk to the process. Here, we report a previously uncovered mechanism of histone mark H3K36me2 in recruiting and activating DNMT3A, primarily in the intergenic regions. Our biochemistry studies discovered that H3K36me2 could be specifically bound by DNMT3A PWWP domain and substantially stimulate DNMT3A activity, representing the first example of histone modification in activating DNMT3A activity. Using multiple myeloma model, KMS11, we further found that the genome-wide gain-of-H3K36me2 resulted in global increase of 5mC, primarily in the intergenic regions. Importantly, DNA inhibitor treatment specifically blocked KMS11 growth demonstrating the functional importance of this regulatory pathway.
2019-12-31 | GSE140302 | GEO
Project description:Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
2022-07-07 | GSE183969 | GEO
Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation
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Project description:Epigenetic modifications on the chromatin do not occur in isolation. Chromatin associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse embryonic stem cell (mESC) model to describe in detail the relationships within the H3K27-H3K36-DNA methylation subnetwork. In particular, we focus on the major epigenetic re-organization caused by deletion of the histone 3 lysine 36 methyltransferase NSD1, which in mESCs deposits nearly all of the intergenic H3K36me2. Although disturbing the H3K27 and DNA methylation (DNAme) components also affects this network to a certain extent, the removal of H3K36me2 has the most drastic effect on the epigenetic landscape, resulting in full intergenic spread of H3K27me3 and a substantial decrease in DNAme. By profiling DNMT3A and CHH methylation (mCHH), we show that H3K36me2 loss upon Nsd1-KO leads to a massive re-distribution of DNMT3A and mCHH away from intergenic regions and towards active gene bodies, suggesting that DNAme reduction is at least in part caused by redistribution of de novo methylation. Additionally, we show that pervasive acetylation of H3K27 is regulated by the interplay of H3K36 and H3K27 methylation. Our analysis highlights the importance of H3K36me2 as a major determinant of the developmental epigenome and provides a framework for further consolidating our knowledge of epigenetic networks.
2022-03-28 | GSE186506 | GEO
Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [ChIP-seq]
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Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [MeDIP-Seq]
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