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H2A.Z对雌性小鼠的卵母细胞成熟和生育能力至关重要。

H2A.Z is essential for oocyte maturation and fertility in female mouse.

作者信息

Xu Qianhua, Huang Chunyi, Ming Jia, Lu Xukun, Liu Ling, Du Zhenhai, Chen Zhen, Na Jie, Li Guohong, Xiang Yunlong, Zhang Yu, Xie Wei

机构信息

Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.

Tsinghua-Peking Center for Life Sciences, Beijing, China.

出版信息

Nat Struct Mol Biol. 2025 Jun 13. doi: 10.1038/s41594-025-01580-y.

DOI:10.1038/s41594-025-01580-y
PMID:40514538
Abstract

Oocyte maturation is essential for both gametogenesis and early development, when large amounts of transcripts are produced without DNA replication. Histone variants, which can be incorporated at cis-regulatory elements in a replication-independent manner, are naturally suited for such regulation. However, their roles during mammalian oocyte maturation remain elusive. Here we show that oocyte-specific depletion of H2A.Z, an evolutionarily conserved histone variant, in female mice results in profound epigenetic and transcriptional alterations, impedes resumption of oocyte meiosis II and causes infertility. Mechanistically, H2A.Z in mouse oocytes is incorporated into chromatin at active promoters and putative enhancers. Interestingly, H2A.Z is depleted from CG-rich silenced promoters, including poised Polycomb target genes, in fully grown oocytes (FGOs), unlike what occurs in growing oocytes, early embryos and mouse embryonic stem cells. In FGOs, the presence of H2A.Z correlates with histone acetylation, except in regions marked by DNA methylation and H3K36me3. Depletion of H2A.Z leads to impaired activities of a subset of promoters and enhancers, correlated with defective gene expression. Consistent with a role in gene activation, H2A.Z in FGOs is widely acetylated at the promoters and enhancers. Together, our findings uncover an essential role of H2A.Z in mammalian oocyte maturation and female fertility.

摘要

卵母细胞成熟对于配子发生和早期发育都至关重要,在此过程中会在没有DNA复制的情况下产生大量转录本。组蛋白变体能够以不依赖复制的方式整合到顺式调控元件中,天然适合于这种调控。然而,它们在哺乳动物卵母细胞成熟过程中的作用仍然不清楚。在这里,我们表明,雌性小鼠中卵母细胞特异性缺失H2A.Z(一种进化上保守的组蛋白变体)会导致深刻的表观遗传和转录改变,阻碍卵母细胞减数分裂II的恢复并导致不育。从机制上讲,小鼠卵母细胞中的H2A.Z会整合到活跃启动子和假定增强子处的染色质中。有趣的是,与生长中的卵母细胞、早期胚胎和小鼠胚胎干细胞不同,在完全成熟的卵母细胞(FGOs)中,富含CG的沉默启动子(包括处于就绪状态的多梳靶基因)中没有H2A.Z。在FGOs中,H2A.Z的存在与组蛋白乙酰化相关,但在DNA甲基化和H3K36me3标记的区域除外。H2A.Z的缺失会导致一部分启动子和增强子的活性受损,这与基因表达缺陷相关。与在基因激活中的作用一致,FGOs中的H2A.Z在启动子和增强子处广泛乙酰化。总之,我们的发现揭示了H2A.Z在哺乳动物卵母细胞成熟和雌性生育中的重要作用。

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1
H2A.Z is essential for oocyte maturation and fertility in female mouse.H2A.Z对雌性小鼠的卵母细胞成熟和生育能力至关重要。
Nat Struct Mol Biol. 2025 Jun 13. doi: 10.1038/s41594-025-01580-y.
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H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes.H2A.Z增强母源H3K4me3的形成,对小鼠卵母细胞减数分裂进程至关重要。
Nat Struct Mol Biol. 2025 Jun 13. doi: 10.1038/s41594-025-01573-x.
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Analysis of active chromatin modifications in early mammalian embryos reveals uncoupling of H2A.Z acetylation and H3K36 trimethylation from embryonic genome activation.早期哺乳动物胚胎中活性染色质修饰的分析表明,H2A.Z 乙酰化和 H3K36 三甲基化与胚胎基因组激活的解耦。
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The histone variant H2A.Z is an important regulator of enhancer activity.组蛋白变体H2A.Z是增强子活性的重要调节因子。
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H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs.H2A.Z.1单泛素化拮抗BRD2以维持胚胎干细胞中处于平衡状态的染色质。
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Oxoglutarate dehydrogenase and acetyl-CoA acyltransferase 2 selectively associate with H2A.Z-occupied promoters and are required for histone modifications.草酰琥珀酸脱氢酶和乙酰辅酶 A 酰基转移酶 2 选择性地与 H2A.Z 占据的启动子结合,并且对于组蛋白修饰是必需的。
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本文引用的文献

1
Mapping putative enhancers in mouse oocytes and early embryos reveals TCF3/12 as key folliculogenesis regulators.在小鼠卵母细胞和早期胚胎中绘制假定增强子图谱,揭示 TCF3/12 作为关键的卵泡发生调控因子。
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SWI/SNF-dependent genes are defined by their chromatin landscape.SWI/SNF依赖基因由其染色质景观定义。
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PGE alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate.
PGE 通过 H2A.Z 变体增强子核小体修饰来改变染色质,从而促进造血干细胞命运。
Proc Natl Acad Sci U S A. 2023 May 9;120(19):e2220613120. doi: 10.1073/pnas.2220613120. Epub 2023 May 1.
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Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation.Tip60 介导的 H2A.Z 乙酰化促进神经元命运特化和二价基因激活。
Mol Cell. 2022 Dec 15;82(24):4627-4646.e14. doi: 10.1016/j.molcel.2022.11.002. Epub 2022 Nov 22.
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CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos.CBP/p300 和组蛋白去乙酰化酶活性调节小鼠胚胎植入前胚胎中 H3K27 的乙酰化动力学和胚胎基因组激活。
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Neurotransmitters, neuropeptides and calcium in oocyte maturation and early development.神经递质、神经肽与钙在卵母细胞成熟和早期发育中的作用
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Modulation of cellular processes by histone and non-histone protein acetylation.组蛋白和非组蛋白蛋白乙酰化对细胞过程的调节。
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Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos.早期斑马鱼胚胎中有序多梳复合物募集建立发育基因沉默。
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The H2A.Z-nuclesome code in mammals: emerging functions.哺乳动物中的 H2A.Z-核小体编码:新兴功能。
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Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia.Tip60 通过乙酰化 H2A.Z 激活 Hoxa9 和 Meis1 的表达,促进 MLL-AF10 和 MLL-ENL 急性髓系白血病。
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