Similar Datasets
Project description: Not available
| S-EPMC6954886 | biostudies-literature
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:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation
| PRJNA589268 | ENA
Project description:Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1-4. They are also implicated in human developmental disorders and cancers5-8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9-11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
| S-EPMC6742567 | biostudies-literature
Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [RNA-seq]
| PRJNA589273 | ENA
Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [MeDIP-Seq]
| PRJNA589274 | ENA
Project description:DNMT3A Reads and Connects Histone H3K36me2 to DNA methylation [ChIP-seq]
| PRJNA589275 | ENA
Project description:The Dnmt3a DNA methyltransferase contains in its N-terminal part a PWWP domain that is involved in chromatin targeting. Here, we have investigated the interaction of the PWWP domain with modified histone tails using peptide arrays and show that it specifically recognizes the histone 3 lysine 36 trimethylation mark. H3K36me3 is known to be a repressive modification correlated with DNA methylation in mammals and heterochromatin in Schizosaccharomyces pombe. These results were confirmed by equilibrium peptide binding studies and pulldown experiments with native histones and purified native nucleosomes. The PWWP-H3K36me3 interaction is important for the subnuclear localization of enhanced yellow fluorescent protein-fused Dnmt3a. Furthermore, the PWWP-H3K36me3 interaction increases the activity of Dnmt3a for methylation of nucleosomal DNA as observed using native nucleosomes isolated from human cells after demethylation of the DNA with 5-aza-2'-deoxycytidine as substrate for methylation with Dnmt3a. These data suggest that the interaction of the PWWP domain with H3K36me3 is involved in targeting of Dnmt3a to chromatin carrying that mark, a model that is in agreement with several studies on the genome-wide distribution of DNA methylation and H3K36me3.
| S-EPMC2924014 | biostudies-literature