Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1^LSH/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 Å 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 MET1^Dnmt1, 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.

核小体会阻止 DNA 甲基转移酶的进入，除非它们通过 DNA 甲基化 1 (DDM1 ^{LSH / HELLS} ) 的减少进行重塑，DNA 甲基化 1 是表观遗传遗传的类似 Snf2 的主要调节因子。我们发现 DDM1 促进组蛋白变体 H3.3 被 H3.1 取代。在ddm1突变体中，H3.3 伴侣蛋白 HIRA 的缺失使 DNA 甲基化部分恢复，而 H3.1 伴侣蛋白 CAF-1 变得至关重要。具有变体核小体的 DDM1 3.2 Å 处的单颗粒冷冻电镜结构揭示了与组装所需残基附近的组蛋白 H3.3 以及与未修饰的 H4 尾部的结合。 N 端自动抑制结构域抑制活性，而解旋酶结构域中的二硫键支持活性。 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。雄性种系 H3.3 变体 MGH3/HTR10 可抵抗 DDM1 的重塑，并充当精子细胞中表观遗传的占位核小体。