HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.
HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.
复制标题
HDAC3 通过在精子发生减数分裂出口处的酶独立转录调节来控制男性生育力。
DOI：
10.1093/nar/gkab313
复制
发表时间：
2021-05-21
影响因子：
14.9
通讯作者：
Ye L
中科院分区：
文献类型：
--
作者：
Yin H;Kang Z;Zhang Y;Gong Y;Liu M;Xue Y;He W;Wang Y;Zhang S;Xu Q;Fu K;Zheng B;Xie J;Zhang J;Wang Y;Lin M;Zhang Y;Feng H;Xin C;Guan Y;Huang C;Guo X;Wang PJ;Baur JA;Zheng K;Sun Z;Ye L
摘要精母细胞减数分裂后向单倍体生殖细胞的转变是精子发生的重要步骤。这种转变背后的表观基因组调控机制仍不清楚。在这里，我们发现一个突出的转录开关从晚期精母细胞早期圆形精子细胞减数分裂到减数分裂后的过渡，这是与强大的组蛋白乙酰化的变化在整个基因组。在组蛋白去乙酰化酶（HDACs）和乙酰转移酶中，我们发现HDAC 3选择性地在减数分裂晚期和单倍体早期表达。睾丸特异性敲除HDAC 3的三个独立小鼠品系显示不育和减数分裂退出缺陷，在减数分裂晚期或圆形精子细胞早期停滞。阶段特异性RNA-seq和组蛋白乙酰化ChIP-seq分析表明，HDAC 3抑制减数分裂/精原基因，并在减数分裂退出期间激活减数分裂后单倍体基因程序，并伴有相关的组蛋白乙酰化改变。出乎意料的是，通过核受体辅阻遏物（NCOR或SMRT）中的错义突变消除HDAC 3催化活性不会导致不育，尽管HDAC 3敲除会导致组蛋白过度乙酰化，这表明HDAC 3酶活性不是精子发生所需的。对睾丸中HDAC 3顺式组的模体分析鉴定了SOX 30，其在精子发生期间具有与HDAC 3相似的时空表达模式。睾丸中SOX 30的消耗消除了HDAC 3向结合位点的基因组募集。总的来说，这些结果建立了SOX 30/HDAC 3信号作为一个关键的调节器的转录程序中的脱乙酰酶独立的方式在减数分裂到减数分裂后的精子发生的过渡。
Abstract The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.
登录
查看更多内容
影响因子：
64.8
作者：
Alenghat, Theresa;Meyers, Katherine;Mullican, Shannon E.;Leitner, Kirstin;Adeniji-Adele, Adetoun;Avila, Jacqueline;Bucan, Maja;Ahima, Rexford S.;Kaestner, Klaus H.;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.
影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
4.6
作者：
Feng CA;Spiller C;Merriner DJ;O'Bryan MK;Bowles J;Koopman P
通讯作者：
Koopman P
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
7.7
作者：
Davis MP;Carrieri C;Saini HK;van Dongen S;Leonardi T;Bussotti G;Monahan JM;Auchynnikava T;Bitetti A;Rappsilber J;Allshire RC;Shkumatava A;O'Carroll D;Enright AJ
通讯作者：
Enright AJ