Structural insight into autoinhibition and histone H3-induced activation of DNMT3A

• Published in: Nature (London) 2015-01, Vol.517 (7536), p.640-644
• Main Authors: Guo, Xue, Wang, Ling, Li, Jie, Ding, Zhanyu, Xiao, Jianxiong, Yin, Xiaotong, He, Shuang, Shi, Pan, Dong, Liping, Li, Guohong, Tian, Changlin, Wang, Jiawei, Cong, Yao, Xu, Yanhui
• Format: Article
• Language: English
• Subjects: 631/208/176/1988; 631/535/1266; 82/16; 82/83; Animals; Catalytic Domain; Crystallography, X-Ray; Crystals; Deoxyribonucleic acid; Developmental stages; DNA; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - chemistry; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA - metabolism; DNA Methylation; Embryonic growth stage; Enzymatic activity; Enzyme Activation; Epigenetic inheritance; Genetic aspects; Genetic research; Genomics; Histones; Histones - chemistry; Histones - metabolism; Humanities and Social Sciences; Humans; letter; Mammals; Methylation; Methyltransferases; Mice; Microscopy; Models, Molecular; multidisciplinary; Mutation; Peptides; Physiological aspects; Protein Structure, Tertiary; Proteins; Science; Structure; Xenopus laevis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13899

A working model for histone H3-induced dynamic regulation of the de novo DNA methyltransferase. DNA methyltransferase autoinhibition and activation DNA methylation is established during embryogenesis by the de novo DNA methyltransferases DNMT3A and DNMT3B. Here, Yanhui Xu and colleagues determine crystal structures of DNMT3L (a catalytically inactive DNMT3 paralogue that stimulates the enzymatic activity of Dnmt3a) bound to DNMT3A and histone H3. The structure reveals an unexpected autoinhibitory conformation in the absence of histone H3, and a mechanism of H3-induced activation. DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance 1 , 2 , 3 , 4 , 5 . Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B 6 , 7 , 8 , and the methylation patterns vary with developmental stages and cell types 9 , 10 , 11 , 12 . DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a 13 . Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation 14 . The ATRX–DNMT3–DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0) 15 , 16 , 17 . The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro 17 , 18 , 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 meth