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Gcn5-Mediated Histone Acetylation Governs Nucleosome Dynamics in Spermiogenesis.
Developmental Cell ( IF 10.7 ) Pub Date : 2019-11-21 , DOI: 10.1016/j.devcel.2019.10.024
Lacey J Luense 1 , Greg Donahue 1 , Enrique Lin-Shiao 2 , Richard Rangel 1 , Angela H Weller 1 , Marisa S Bartolomei 3 , Shelley L Berger 4
Affiliation  

During mammalian spermatogenesis, germ cell chromatin undergoes dramatic histone acetylation-mediated reorganization, whereby 90%-99% of histones are evicted. Given the potential role of retained histones in fertility and embryonic development, the genomic location of retained nucleosomes is of great interest. However, the ultimate position and mechanisms underlying nucleosome eviction or retention are poorly understood, including several studies utilizing micrococcal-nuclease sequencing (MNase-seq) methodologies reporting remarkably dissimilar locations. We utilized assay for transposase accessible chromatin sequencing (ATAC-seq) in mouse sperm and found nucleosome enrichment at promoters but also retention at inter- and intragenic regions and repetitive elements. We further generated germ-cell-specific, conditional knockout mice for the key histone acetyltransferase Gcn5, which resulted in abnormal chromatin dynamics leading to increased sperm histone retention and severe reproductive phenotypes. Our findings demonstrate that Gcn5-mediated histone acetylation promotes chromatin accessibility and nucleosome eviction in spermiogenesis and that loss of histone acetylation leads to defects that disrupt male fertility and potentially early embryogenesis.

中文翻译:

Gcn5介导的组蛋白乙酰化控制精子发生中的核小体动力学。

在哺乳动物的精子发生过程中,生殖细胞染色质经历了剧烈的组蛋白乙酰化介导的重组,从而驱逐了90%-99%的组蛋白。考虑到保留的组蛋白在生育力和胚胎发育中的潜在作用,保留的核小体的基因组位置引起人们极大的兴趣。然而,对核小体驱逐或保留的最终位置和机制了解甚少,包括几项利用微球菌核酸酶测序(MNase-seq)方法进行的研究,报告了明显不同的位置。我们利用小鼠精子中的转座酶可及染色质测序(ATAC-seq)进行测定,发现启动子处的核小体富集,但在基因间和基因内区域以及重复元件中也保留了。我们进一步产生了生殖细胞特异性的 条件敲除小鼠的关键组蛋白乙酰转移酶Gcn5,导致染色质动力学异常,导致精子组蛋白保留增加和严重的生殖表型。我们的发现表明,Gcn5介导的组蛋白乙酰化促进了精子发生过程中的染色质可及性和核小体驱逐,组蛋白乙酰化的丧失导致了破坏男性生育力和潜在的早期胚胎发生的缺陷。
更新日期:2019-11-22
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