本期文章：《细胞》：Online/在线发表

DDM1对组蛋白H3变体的染色质重塑是DNA甲基化表观遗传的基础，这一成果由美国霍华德休斯医学研究所Robert A. Martienssen和Leemor Joshua-Tor团队合作经过不懈努力而取得。2023年8月28日出版的《细胞》杂志发表了这一最新研究成果。

研究人员表明DDM1促进H3.1取代组蛋白变体H3.3。在ddm1突变体中，DNA甲基化通过H3.3伴侣HIRA的缺失部分恢复，并且H3.1伴侣CAF-1必不可少。具有变异核小体DDM1的3.2 Å单粒子冷冻电镜结构表明组装所需残基附近的组蛋白H3.3和未修饰的H4尾部结合。N端自抑制结构域抑制其活性，而解旋酶结构域中的二硫键具有支持活性。

DDM1在细胞周期中与H3.1和H3.3以及DNA甲基转移酶MET1^Dnmt1共定位，但被H4K16乙酰化阻断。雄性个体中H3.3变体MGH3/HTR10对DDM1介导的重塑具有抗性，并在精子细胞作为placeholder核小体介导表观遗传。

据了解，核小体会阻断DNA甲基转移酶，除非它们被DNA甲基化1（DDM1^LSH/HELLS）中的DECREASE重塑，这是一种类似Snf2的表观遗传主调节因子。

附：英文原文

Title: Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation

Author: Seung Cho Lee, Dexter W. Adams, Jonathan J. Ipsaro, Jonathan Cahn, Jason Lynn, Hyun-Soo Kim, Benjamin Berube, Viktoria Major, Joseph P. Calarco, Chantal LeBlanc, Sonali Bhattacharjee, Umamaheswari Ramu, Daniel Grimanelli, Yannick Jacob, Philipp Voigt, Leemor Joshua-Tor, Robert A. Martienssen

Issue&Volume: 2023-08-28

Abstract: Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1LSH/HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance.

DOI: 10.1016/j.cell.2023.08.001