Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
Abstract
DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.
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Promoter H3K4me3 inhibits DNMT3a activity, preventing methylation at CpG islands.
“Promoter H3K4me3, in turn, inhibits the activity of the de novo DNA methyltransferase DNMT3a thus preventing methylation at CGIs (20).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [20]
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“Once the DNMT3A–DNMT3L complex is recruited to the nucleosome, unmethylated H3K4 binds to the ADD domain and stimulates DNMT3A to undergo a significant conformational change from an autoinhibitory form to an active form that can bind DNA and exert DNA methylation activity [85].”
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- Authors
- Guo, X., Wang, L., Li, J., Ding, Z., Xiao, J., Yin, X., He, S., Shi, P., Dong, L., Li, G., Tian, C., Wang, J., Cong, Y., & Xu, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Chinese Academy of Sciences (CN)
- University of Science and Technology of China (CN)
- Tsinghua University (CN)
- Corresponding author
- Xu, Yanhui
- ORCID
- Venue
- Nature
- Published
- 2014-11-10
- Volume
- 517
- Issue
- 7536
- Pages
- 640-644
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2084099620
- Cited by
- 361
- References
- 43
- Citations by year
- 2026: 26 · 2025: 19 · 2024: 32 · 2023: 24 · 2022: 40 · 2021: 28 · 2020: 38 · 2019: 36 · 2018: 21 · 2017: 27 · 2016: 46 · 2015: 24
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 › Molecular Biology › Cancer-related gene regulation
- Keywords
- DNMT3A, DNMT3L, histone H3, autoinhibition, de novo methylation, catalytic domain, H3K4me3, crystal structure, epigenetic regulation, embryonic development, DNA binding affinity, histone modifications
- MeSH terms
- DNA Methyltransferase 3A, Animals, DNA, DNA (Cytosine-5-)-Methyltransferases, Enzyme Activation, Histones, Humans, Models, Molecular, Xenopus laevis, Protein Structure, Tertiary, Crystallography, X-Ray, DNA Methylation, Catalytic Domain, Mice
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