Nashun Buhe, Hill Peter W S, Smallwood Sebastien A, Dharmalingam Gopuraja, Amouroux Rachel, Clark Stephen J, Sharma Vineet, Ndjetehe Elodie, Pelczar Pawel, Festenstein Richard J, Kelsey Gavin, Hajkova Petra
Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
Mol Cell. 2015 Nov 19;60(4):611-25. doi: 10.1016/j.molcel.2015.10.010. Epub 2015 Nov 5.
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.
染色质的完整性为真核生物中所有与DNA相关的过程提供了一个动态模板，它通过依赖复制和不依赖复制的组装途径得以维持。为了研究在没有DNA复制的情况下组蛋白沉积的作用，我们在发育中的小鼠卵母细胞中删除了H3.3伴侣蛋白Hira。我们发现，非复制性发育卵母细胞的染色质是动态的，缺乏持续的H3.3/H4沉积会改变染色质结构，导致DNase I敏感性增加、DNA损伤积累以及严重的生育表型。在分子水平上，异常的染色质结构会导致基因表达动态范围急剧下降、出现假转录本以及从头DNA甲基化效率低下。因此，我们的研究明确表明了在体内非复制系统中，持续的组蛋白替换和染色质稳态对于转录调控和正常发育进程的重要性。
