Structural Basis for the H2AK119ub1-specific DNMT3A-nucleosome Interaction

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jul 23

PMID 39043678

Authors

Xinyi Chen

Yiran Guo

Ting Zhao

Jiuwei Lu

Jian Fang

Yinsheng Wang

Gang Greg Wang

Jikui Song

Affiliations

Soon will be listed here.

Abstract

Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1-nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1's ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR's interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural and biochemical analysis also reveals competition between DNMT3A1 and JARID2, a cofactor of polycomb repression complex 2 (PRC2), for nucleosome binding, suggesting the interplay between different epigenetic pathways. Together, this study reports a molecular basis for H2AK119ub1-dependent DNMT3A1-nucleosome association, with important implications in DNMT3A1-mediated DNA methylation in development.

Citing Articles

The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment.

Wapenaar H, Clifford G, Rolls W, Pasquier M, Burdett H, Zhang Y EMBO Rep. 2024; 25(12):5743-5779.

PMID: 39528729 PMC: 11624362. DOI: 10.1038/s44319-024-00306-3.

Using human disease mutations to understand de novo DNA methyltransferase function.

Rolls W, Wilson M, Sproul D Biochem Soc Trans. 2024; 52(5):2059-2075.

PMID: 39446312 PMC: 11555716. DOI: 10.1042/BST20231017.

References

Heyn P, Logan C, Fluteau A, Challis R, Auchynnikava T, Martin C . Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2018; 51(1):96-105. PMC: 6520989. DOI: 10.1038/s41588-018-0274-x. View

Du J, Johnson L, Jacobsen S, Patel D . DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol. 2015; 16(9):519-32. PMC: 4672940. DOI: 10.1038/nrm4043. View

Chen B, Chan W . The de novo DNA methyltransferase DNMT3A in development and cancer. Epigenetics. 2014; 9(5):669-77. PMC: 4063825. DOI: 10.4161/epi.28324. View

Baylin S . DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005; 2 Suppl 1:S4-11. DOI: 10.1038/ncponc0354. View

Cooper S, Grijzenhout A, Underwood E, Ancelin K, Zhang T, Nesterova T . Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2. Nat Commun. 2016; 7:13661. PMC: 5133711. DOI: 10.1038/ncomms13661. View

Yuan W, Xu M, Huang C, Liu N, Chen S, Zhu B . H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J Biol Chem. 2011; 286(10):7983-7989. PMC: 3048685. DOI: 10.1074/jbc.M110.194027. View

Bourchis D, Xu G, Lin C, Bollman B, Bestor T . Dnmt3L and the establishment of maternal genomic imprints. Science. 2001; 294(5551):2536-9. DOI: 10.1126/science.1065848. View

Bepler T, Morin A, Rapp M, Brasch J, Shapiro L, Noble A . Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs. Nat Methods. 2019; 16(11):1153-1160. PMC: 6858545. DOI: 10.1038/s41592-019-0575-8. View

Jones P, Gonzalgo M . Altered DNA methylation and genome instability: a new pathway to cancer?. Proc Natl Acad Sci U S A. 1997; 94(6):2103-5. PMC: 33658. DOI: 10.1073/pnas.94.6.2103. View

10.

Cedar H, Bergman Y . Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009; 10(5):295-304. DOI: 10.1038/nrg2540. View

11.

Neri F, Krepelova A, Incarnato D, Maldotti M, Parlato C, Galvagni F . Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell. 2013; 155(1):121-34. DOI: 10.1016/j.cell.2013.08.056. View

12.

Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M . Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 2009; 10(11):1235-41. PMC: 2775176. DOI: 10.1038/embor.2009.218. View

13.

Li E, Beard C, Jaenisch R . Role for DNA methylation in genomic imprinting. Nature. 1993; 366(6453):362-5. DOI: 10.1038/366362a0. View

14.

Stark H . GraFix: stabilization of fragile macromolecular complexes for single particle cryo-EM. Methods Enzymol. 2010; 481:109-26. DOI: 10.1016/S0076-6879(10)81005-5. View

15.

Weinberg D, Rosenbaum P, Chen X, Barrows D, Horth C, Marunde M . Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands. Nat Genet. 2021; 53(6):794-800. PMC: 8283687. DOI: 10.1038/s41588-021-00856-5. View

16.

Li G, Margueron R, Ku M, Chambon P, Bernstein B, Reinberg D . Jarid2 and PRC2, partners in regulating gene expression. Genes Dev. 2010; 24(4):368-80. PMC: 2816736. DOI: 10.1101/gad.1886410. View

17.

Jani K, Jain S, Ge E, Diehl K, Lundgren S, Muller M . Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase. Proc Natl Acad Sci U S A. 2019; 116(17):8295-8300. PMC: 6486736. DOI: 10.1073/pnas.1819029116. View

18.

Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S . Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014; 46(4):385-8. PMC: 3981653. DOI: 10.1038/ng.2917. View

19.

Li B, Huang Z, Cui Q, Song X, Du L, Jeltsch A . Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res. 2011; 21(8):1172-81. PMC: 3193484. DOI: 10.1038/cr.2011.92. View

20.

Morgan M, Haj-Yahya M, Ringel A, Bandi P, Brik A, Wolberger C . Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science. 2016; 351(6274):725-8. PMC: 4863942. DOI: 10.1126/science.aac5681. View