DDM1对组蛋白H3变体的染色质重塑是DNA甲基化的表观遗传的基础。

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2023-09-14 Epub Date: 2023-08-28 DOI:10.1016/j.cell.2023.08.001

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

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引用次数: 2

摘要

核小体阻断DNA甲基转移酶的通路，除非它们被DNA甲基化1（DDM1LSH/HELLS）中的DECREASE（表观遗传的Snf2样主调节因子）重塑。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，DNA甲基化通过H3.3伴侣HIRA的缺失而部分恢复，而H3.1伴侣CAF-1变得必不可少。具有变体核小体的DDM1 3.2Å处的单颗粒冷冻EM结构揭示了与组装所需的组蛋白H3.3近残基以及与未修饰的H4尾部的结合。N-末端的自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共定位，并与DNA甲基转移酶MET1Dnmt1共定位，但被H4K16乙酰化阻断。雄性种系H3.3变体MGH3/HTR10对DDM1的重塑具有抗性，并在精子细胞中充当表观遗传的占位符核小体。

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

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.

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.