Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.
Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.
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DOI：
10.1016/j.molcel.2015.10.010
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发表时间：
2015-11-19
期刊：
影响因子：
16
通讯作者：
Hajkova P
中科院分区：
文献类型：
--
作者：
Nashun B;Hill PW;Smallwood SA;Dharmalingam G;Amouroux R;Clark SJ;Sharma V;Ndjetehe E;Pelczar P;Festenstein RJ;Kelsey G;Hajkova P
染色质的完整性是通过复制依赖和独立的组装途径来维持的，它为真核生物中所有与DNA相关的过程提供了一个动态模板。为了解决组蛋白沉积在没有DNA复制的情况下的作用，我们在小鼠卵母细胞发育过程中删除了H3.3伴侣Hira。我们发现，非复制型发育中的卵母细胞染色质是动态的，缺乏连续的H3.3/H4沉积会改变染色质结构，导致DNase I敏感性增加，DNA损伤累积，并出现严重的生育表型。在分子水平上，染色质结构异常导致基因表达的动态范围急剧下降，假转录本的出现，以及无效的从头DNA甲基化。因此，我们的研究明确地表明，在体内的非复制系统中，持续的组蛋白替代和染色质动态平衡对于转录调节和正常发育进程具有重要意义。组蛋白H3/H4替换是连续的，并由Hira在小鼠卵子发生期间介导。Hira的丢失导致染色质异常和广泛的卵母细胞丢失，Hira的耗尽减少了组蛋白负载，这阻止了正常的转录调节，Hira介导组蛋白替换是卵母细胞正常5mC沉积所必需的，以解决基本细胞过程在多大程度上依赖于体内复制独立的染色质组装，Nashun等人等人。在小鼠卵子发生过程中缺失了组蛋白H3.3伴侣基因Hira。他们的结果表明，持续的组蛋白替代、染色质动态平衡、转录调控和从头DNA甲基化之间存在关键关系。
The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo. Histone H3/H4 replacement is continuous and mediated by Hira during mouse oogenesis Loss of Hira results in chromatin abnormalities and extensive oocyte loss Hira depletion reduces histone load, which prevents normal transcriptional regulation Hira-mediated histone replacement is required for normal 5mC deposition in oocytes To address the extent to which basic cellular processes depend on replication-independent chromatin assembly in vivo, Nashun et al. deleted histone H3.3 chaperone Hira during mouse oogenesis. Their results demonstrate a critical relationship between continuing histone replacement, chromatin homeostasis, transcriptional regulation, and de novo DNA methylation.