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The Histone Mark H3k36me2 Recruits DNMT3A and Shapes the Intergenic DNA Methylation Landscape Daniel N

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The Histone Mark H3k36me2 Recruits DNMT3A and Shapes the Intergenic DNA Methylation Landscape Daniel N LETTER https://doi.org/10.1038/s41586-019-1534-3 The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape Daniel N. Weinberg1,12, Simon Papillon-Cavanagh2,12, Haifen Chen2, Yuan Yue3, Xiao Chen4,5, Kartik N. Rajagopalan6, Cynthia Horth2, John T. McGuire4,5, Xinjing Xu4,5, Hamid Nikbakht2, Agata E. Lemiesz1, Dylan M. Marchione7,8, Matthew R. Marunde9, Matthew J. Meiners9, Marcus A. Cheek9, Michael-Christopher Keogh9, Eric Bareke2, Anissa Djedid2, Ashot S. Harutyunyan2, Nada Jabado2,10,11, Benjamin A. Garcia7,8, Haitao Li3, C. David Allis1,13*, Jacek Majewski2,13* & Chao Lu4,5,13* Enzymes that catalyse CpG methylation in DNA, including the sequencing (WGBS) at high coverage (840 million reads; 45× coverage). DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B Enriched regions of H3K36me2 and H3K36me3 were in close proxim- (DNMT3B), are indispensable for mammalian tissue development ity to one another, and together defined domains greater than 1 Mb in and homeostasis1–4. They are also implicated in human size that were largely exclusive from domains demarcated by H3K9me3 developmental disorders and cancers5–8, supporting the critical and H3K27me3 (Fig. 1a). H3K36me2 levels positively correlated with role of DNA methylation in the specification and maintenance of CpG methylation, and on the basis of this histone post-translational cell fate. Previous studies have suggested that post-translational modification, together with H3K27me3 and H3K9me3, the genome modifications of histones are involved in specifying patterns of could be partitioned into regions of high (75%; H3K36me2), interme- DNA methyltransferase localization and DNA methylation at diate (50%; H3K27me3) and low (30%; H3K9me3) levels of CpG meth- promoters and actively transcribed gene bodies9–11. However, the ylation (Fig. 1a, Extended Data Fig. 1a, b). Furthermore, DNMT3A and mechanisms that control the establishment and maintenance of DNMT3B ChIP–seq reads were predominantly observed in H3K36me2 intergenic DNA methylation remain poorly understood. Tatton– and H3K36me3 domains (Fig. 1a, Extended Data Fig. 1b), which sug- Brown–Rahman syndrome (TBRS) is a childhood overgrowth gests that the high levels of CpG methylation in these regions are—at disorder that is defined by germline mutations in DNMT3A. TBRS least in part—a result of the preferential recruitment of DNMT3A and shares clinical features with Sotos syndrome (which is caused by DNMT3B. Additional chromatin features that were associated with haploinsufficiency of NSD1, a histone methyltransferase that these domains of high levels of H3K36 and CpG methylation included catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), higher levels of H3K27ac and H3K4me1, as well as increased gene which suggests that there is a mechanistic link between these expression—consistent with previous reports that linked H3K36me2 two diseases. Here we report that NSD1-mediated H3K36me2 is and H3K36me3 to active gene transcription14,15 (Fig. 1b, Extended Data required for the recruitment of DNMT3A and maintenance of DNA Fig. 1c). Moreover, the regions with high levels of H3K36 and CpG methylation at intergenic regions. Genome-wide analysis shows that methylation corresponded to compartments and topologically asso- the binding and activity of DNMT3A colocalize with H3K36me2 ciated domains derived from chromatin conformation capture (Hi-C) at non-coding regions of euchromatin. Genetic ablation of Nsd1 studies of mouse myoblasts16 (Extended Data Fig. 1d), suggesting that and its paralogue Nsd2 in mouse cells results in a redistribution of these modifications together define transcriptionally active euchro- DNMT3A to H3K36me3-modified gene bodies and a reduction in matin that is spatially segregated from constitutive and facultative the methylation of intergenic DNA. Blood samples from patients heterochromatin. with Sotos syndrome and NSD1-mutant tumours also exhibit Our observations are consistent with previous reports that suggest that hypomethylation of intergenic DNA. The PWWP domain of H3K36me3 mediates the targeting of DNMT3B activity10,11. However, DNMT3A shows dual recognition of H3K36me2 and H3K36me3 as this interaction is confined to gene bodies, we hypothesized that an in vitro, with a higher binding affinity towards H3K36me2 that additional chromatin trans-regulatory pathway may act in parallel to is abrogated by TBRS-derived missense mutations. Together, our facilitate CpG methylation at euchromatic regions. On closer exami- study reveals a trans-chromatin regulatory pathway that connects nation, we observed that, whereas H3K36me3 exhibited characteristic aberrant intergenic CpG methylation to human neoplastic and enrichment within gene bodies, H3K36me2 showed a more-diffuse developmental overgrowth. distribution that encompassed both genic and intergenic regions To characterize the role of post-translational modifications of his- (Fig. 1a, Extended Data Fig. 2a, b). Within actively transcribed genes, tones in regulating DNA methyltransferase (DNMT) targeting and H3K36me2 covered areas downstream of the transcriptional start site CpG methylation, we profiled the genome-wide distribution patterns through the first intron, followed by a marked switch to H3K36me3 of histone post-translational modifications (H3K36me3, H3K36me2, after the first splice junction (Extended Data Fig. 2a–c). Notably, H3K27me3, H3K27ac (acetylation of H3 at K27), H3K9me3 and whereas DNMT3B was enriched within gene bodies that contained H3K4me1), DNMT3A and DNMT3B using chromatin immunopre- H3K36me3 (Extended Data Fig. 2d), the localization of DNMT3A cipitation followed by sequencing (ChIP–seq) in C3H10T1/2 mouse mimicked the distribution of H3K36me2 and spanned broad inter- mesenchymal stem cells (MSCs). We also measured levels of CpG genic regions that did not exhibit discernible levels of H3K36me3 methylation at base-pair resolution using whole-genome bisulfite (Fig. 1a, Extended Data Fig. 2a). The contrast between the targeting 1Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 3MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. 4Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. 5Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. 6Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, New York, NY, USA. 7Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 9EpiCypher Inc, Durham, NC, USA. 10Department of Pediatrics, McGill University, Montreal, Quebec, Canada. 11Research Institute of the McGill University Health Center, Montreal, Quebec, Canada. 12These authors contributed equally: Daniel N. Weinberg, Simon Papillon-Cavanagh. 13 These authors jointly supervised this work: C. David Allis, Jacek Majewski, Chao Lu. *e-mail: [email protected]; [email protected]; [email protected] 12 SEPTEMBER 2019 | VOL 573 | NATURE | 281 RESEARCH LETTER a Chr2: 110.7–116.2 Mb (0–97) H3K36me3 (0–48) H3K36me2 (0–5.98) H3K27me3 H3K9me3 (0–16) (3–30) DNMT3A1 DNMT3B (3–20) CpGme Ano3 Olfr1287 Olfr1303 Chrm5 Ryr3 Mir1954 Fmn1 Aqr Dph6 Meis2 050 100% bc d Correlation ΔReads per bin 20–2 1.0 (H3K36me2–H3K36me3) DNMT3A2 DNMT3B 0.5 3 1 0 c 1.5 −0.5 10.0 −1.0 1.0 3 H3K9me H3K27me3 H3K27a H3K4me H3K36me3 CpGme H3K36me2 7.5 H3K36me2 0.5 2 CpGme 5.0 H3K36me3 0 H3K4me1 2.5 1 (normalized reads per bin) H3K27ac –0.5 2 2 A1 r = 0.867 r = 0.372 H3K27me3 0 0 H3K9me3 –1.0 De novo DNA methylation (% CpG) 0 250 500 750 1,000 0 250 500 750 1,000 DNMT3 –0.5 0 0.5 1.0 Bins ranked by H3K36me2 levels DNMT3B (normalized reads per bin) Fig. 1 | Genome-wide colocalization of DNMT3A, CpG methylation H3K36me2, H3K36me3, H3K27me3, H3K27ac, H3K9me3, H3K4me1 and H3K36me2. a, Genome browser representation of ChIP–seq and CpG methylation. c, ChIP–seq normalized reads per 100-kb bin normalized reads for H3K36me3, H3K36me2, H3K27me3, H3K9me3, for DNMT3A1 (y axis) and DNMT3B (x axis) in mouse MSCs DNMT3A1 and DNMT3B in mouse MSCs at chromosome 2 (Chr2): (n = 25,687). Bins (dots) are colour-coded on the basis of differences 110.7–116.2 Mb. The levels of CpG methylation (CpGme) are depicted as between H3K36me3 and H3K36me2 ChIP–seq reads, to show selective a heat map (blue, low; white, intermediate; red, high) and genes (from the enrichment for H3K36me2 (orange) or H3K36me3 (green). d, De novo RefSeq database) are annotated at the bottom. The shaded areas indicate methylation per bin by DNMT3A2 (brown) or DNMT3B (grey) after H3K36me2-enriched genomic regions. For H3K36me3, H3K36me2 reintroduction into Dnmt1, Dnmt3a and Dnmt3b triple-knockout mouse and DNMT3A, data are representative of two independent ChIP–seq ES cells relative to H3K36me2 (n = 1,000). To generate bins, 1-kb genomic experiments; for H3K27me3, H3K9me3 and DNMT3B, ChIP–seq was tiles (n = 2,462,755) were ranked by H3K36me2 enrichment in ES cells performed once and an independent
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