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DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [MeDIP-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140303 | GEO | 2019/12/31

REPOSITORIES: GEO

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DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [ChIP-seq]

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

DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [RNA-seq]

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H3K36me2 recruits DNMT3A and shapes intergenic DNA methylation landscapes

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.

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Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. ChIP sequencing of H3K36me2 ChIP DNA from KMS11 and TKO2 cells using Illumina Solexa Genome Analyzer II single end sequencing protocol. The experiment contains two biological replicates of H3K36me2 ChIP DNA and input materials from KMS11 and TKO2 cells.

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Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes

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Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 cells stably transduced with control vector in comparison to two independent shRNAs against NSD2. Each cell line is tested in duplicate.

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