H3K36me2 methyltransferase NSD2 orchestrates epigenetic reprogramming during spermatogenesis.
H3K36me2 methyltransferase NSD2 orchestrates epigenetic reprogramming during spermatogenesis.
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DOI：
10.1093/nar/gkac533
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发表时间：
2022-07-08
影响因子：
14.9
通讯作者：
Zhou, Li-quan
中科院分区：
文献类型：
--
作者：
Li, Zhiming;Zhang, Xinzong;Xie, Shiming;Liu, Xingping;Fei, Caifeng;Huang, Xunbin;Tang, Yunge;Zhou, Li-quan
精子发生是由复杂的基因表达程序精确控制的，并由表观遗传重编程驱动，包括组蛋白修饰改变和组蛋白到鱼精蛋白的转变。核受体结合SET结构域蛋白2 （Nsd2）是催化H3K36me2的主要组蛋白甲基转移酶，其在男性生殖细胞发育中的作用尚不清楚。在这里，我们报道了NSD2蛋白在生精细胞中丰富。出生后生殖细胞中Nsd2的条件性缺失会由于精子细胞凋亡和精子发生异常而损害生育能力。Nsd2缺乏导致数千个基因失调，生精细胞中H3K36me2和H3K36me3均显著减少，H3K36me2的占用与种系基因的表达呈正相关。Nsd2缺乏导致生精细胞中H4K16ac升高，可能是通过Nsd2和PSMA8相互作用调控乙酰化组蛋白降解。我们进一步发现，Nsd2缺陷会损害ep300诱导的H4K5/8ac， BRDT识别H4K5/8ac介导组蛋白的清除。因此，组蛋白大部分保留在缺乏nsd2的精子中。此外，Nsd2缺乏增强了鱼精蛋白基因的表达，导致缺乏Nsd2的精子中鱼精蛋白含量增加。因此，我们的发现揭示了以前未被认识到的nsd2依赖性染色质重塑在精子发生过程中的作用，并为表观遗传异常影响男性生殖健康的分子机制提供了线索。
Spermatogenesis is precisely controlled by sophisticated gene expression programs and is driven by epigenetic reprogramming, including histone modification alterations and histone-to-protamine transition. Nuclear receptor binding SET domain protein 2 (Nsd2) is the predominant histone methyltransferase catalyzing H3K36me2 and its role in male germ cell development remains elusive. Here, we report that NSD2 protein is abundant in spermatogenic cells. Conditional loss of Nsd2 in postnatal germ cells impaired fertility owing to apoptosis of spermatocytes and aberrant spermiogenesis. Nsd2 deficiency results in dysregulation of thousands of genes and remarkable reduction of both H3K36me2 and H3K36me3 in spermatogenic cells, with H3K36me2 occupancy correlating positively with expression of germline genes. Nsd2 deficiency leads to H4K16ac elevation in spermatogenic cells, probably through interaction between NSD2 and PSMA8, which regulates acetylated histone degradation. We further reveal that Nsd2 deficiency impairs EP300-induced H4K5/8ac, recognized by BRDT to mediate the eviction of histones. Accordingly, histones are largely retained in Nsd2-deficient spermatozoa. In addition, Nsd2 deficiency enhances expression of protamine genes, leading to increased protamine proteins in Nsd2-deficient spermatozoa. Our findings thus reveal a previously unappreciated role of the Nsd2-dependent chromatin remodeling during spermatogenesis and provide clues to the molecular mechanisms in epigenetic abnormalities impacting male reproductive health.
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影响因子：
--
作者：
Huang C;Zhu B
通讯作者：
Zhu B
影响因子：
30.8
作者：
Shirane, Kenjiro;Miura, Fumihito;Lorincz, Matthew C.
通讯作者：
Lorincz, Matthew C.
影响因子：
4.5
作者：
Gomez-H, Laura;Felipe-Medina, Natalia;Pendas, Alberto M.
通讯作者：
Pendas, Alberto M.
影响因子：
4.5
作者：
Popovic R;Martinez-Garcia E;Giannopoulou EG;Zhang Q;Zhang Q;Ezponda T;Shah MY;Zheng Y;Will CM;Small EC;Hua Y;Bulic M;Jiang Y;Carrara M;Calogero RA;Kath WL;Kelleher NL;Wang JP;Elemento O;Licht JD
通讯作者：
Licht JD
影响因子：
3.5
作者：
Kang, Hee-Bum;Choi, Youngsok;Yoon, Ho-Geun
通讯作者：
Yoon, Ho-Geun