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The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape
Open accessAbstract
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 homeostasis 1-4. They are also implicated in human developmental disorders and cancers 5-8, 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 bodies 9-11. 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.
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“studies have suggested that the patterns of DNA methyltransferase localization, DNA methylation, and actively transcribed gene bodies may be specified by histone modifications.113,114”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [113]
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Metadata
- Authors
- Weinberg, D. N., Papillon-Cavanagh, S., Chen, H., Yue, Y., Chen, X., Rajagopalan, K. N., Horth, C., McGuire, J. T., Xu, X., Nikbakht, H., Lemiesz, A. E., Marchione, D. M., Marunde, M. R., Meiners, M. J., Cheek, M. A., Keogh, M.-C., Bareke, E., Djedid, A., Harutyunyan, A. S., Jabado, N., Garcia, B. A., Li, H., Allis, C. D., Majewski, J., & Lu, C.
- Affiliations
- Rockefeller University (US)
- Center for Life Sciences (CN)
- Columbia University Irving Medical Center (US)
- McGill University (CA)
- University of Pennsylvania (US)
- McGill University Health Centre (CA)
- Corresponding author
- Allis, C. David
- Majewski, Jacek
- ORCID
- Weinberg, Daniel N.
- Chen, Xiao
- Rajagopalan, Kartik N.
- Horth, Cynthia
- Xu, Xinjing
- Nikbakht, Hamid
- Marchione, Dylan M.
- Marunde, Matthew R.
- Meiners, Matthew J.
- Cheek, Marcus A.
- Keogh, Michael-Christopher
- Bareke, Eric
- Djedid, Anissa
- Harutyunyan, Ashot S.
- Jabado, Nada
- Garcia, Benjamin A.
- Li, Haitao
- Allis, C. David
- Majewski, Jacek
- Venue
- Nature
- Published
- 2019-09-04
- Volume
- 573
- Issue
- 7773
- Pages
- 281-286
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6742567
- OpenAlex
- W2972254987
- Cited by
- 524
- References
- 47
- Citations by year
- 2026: 48 · 2025: 66 · 2024: 85 · 2023: 79 · 2022: 95 · 2021: 97 · 2020: 46 · 2019: 7
- FWCI
- 20.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P01CA196539, R00CA212257, F30CA224971, P30CA013696)
- National Institute of General Medical Sciences (T32GM008275, R44GM117683, R44GM116584, T32GM007739)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- H3K36me3, DNMT3A, DNA methylation, intergenic regions, CpG methylation, NSD1, NSD2, PWWP domain, histone modifications, Sotos syndrome, Tatton-Brown-Rahman syndrome, overgrowth disorder, histone methyltransferase
- MeSH terms
- Protein Domains, DNA Methyltransferase 3A, Animals, Cell Line, DNA (Cytosine-5-)-Methyltransferases, Growth Disorders, Histones, Humans, Protein Binding, DNA Methylation, Protein Transport, DNA, Intergenic, Mice, Genome-Wide Association Study, Sotos Syndrome
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