MOF influences meiotic expansion of H2AX phosphorylation and spermatogenesis in mice.
MOF influences meiotic expansion of H2AX phosphorylation and spermatogenesis in mice.
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MOF 影响小鼠 H2AX 磷酸化和精子发生的减数分裂扩张。
DOI：
10.1371/journal.pgen.1007300
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发表时间：
2018-05
期刊：
影响因子：
4.5
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Jiang H;Gao Q;Zheng W;Yin S;Wang L;Zhong L;Ali A;Khan T;Hao Q;Fang H;Sun X;Xu P;Pandita TK;Jiang X;Shi Q
在雄性减数分裂前期Ⅰ观察到三个H_2AX磷酸化（γ H_2AX）波：第一波是ATM依赖的，发生在细丝体，第二波和第三波是ATR依赖的，分别发生在偶丝体和粗丝体。第三波H2 AX磷酸化标记并沉默未突触的染色体。很少有人知道H2 AX磷酸化扩展到精母细胞的染色质区域。在这里，我们报告说，组蛋白乙酰转移酶（HAT）MOF参与所有三波的H2 AX磷酸化扩展。Stra 8-Cre（Mof cKO）对精母细胞中Mof的生殖细胞特异性缺失导致H4 K16 ac的整体缺失。在cKO小鼠的细线期和偶线期精母细胞中，γ H2 AX信号仅沿染色体轴沿着观察到，染色质范围内的H2 AX磷酸化丢失。在Mof cKO小鼠粗线期早中期精母细胞中，约有40%的精母细胞沿着性染色体的非突触轴存在γ H2 AX和MDC 1，但不能扩增，导致减数分裂性染色体失活（MSI）失败。此外，尽管RAD 51被熟练地募集到双链断裂（DSB）位点，但在cKO精母细胞的MOF中观察到DSB修复和交叉形成的缺陷，表明MOF在RAD 51募集后促进减数分裂DSB修复。我们建议，MOF调节男性减数分裂，并参与了所有三波的H2 AX磷酸化从细线期到粗线期阶段，启动ATM和ATR，分别扩大。H2 AX的磷酸化是体细胞DNA损伤反应中的一个公认步骤，也发生在减数分裂期间的生殖细胞中。在精子发生过程中，H2 AX磷酸化调节程序性DSB的形成和修复以及未配对染色体的减数分裂沉默。这些过程中的关键步骤是H2 AX磷酸化沿着染色体扩散到起始位点以外，这是通过一种表征不充分的机制发生的。在这里，我们报告说，MOF是在减数分裂过程中参与H2 AX磷酸化的适当扩大。MOF也影响减数分裂性染色体失活，促进粗线期早期募集MDC 1，但不适合BRCA 1或ATR募集到轴向元件。此外，MOF参与适当的减数分裂重组和雄性生殖细胞发育。除了确定一个新的MOF依赖性步骤来调节H2 AX磷酸化的扩展外，这些发现对表观遗传修饰在减数分裂和人类生殖健康中的作用具有广泛的意义。
Three waves of H2AX phosphorylation (γH2AX) have been observed in male meiotic prophase I: the first is ATM-dependent and occurs at leptonema, while the second and third are ATR-dependent, occuring at zygonema and pachynema, respectively. The third wave of H2AX phosphorylation marks and silences unsynapsed chromosomes. Little is known about H2AX phosphorylation expands to chromatin-wide regions in spermatocytes. Here, we report that histone acetyltransferase (HAT) MOF is involved in all three waves of H2AX phosphorylation expansion. Germ cell-specific deletion of Mof in spermatocytes by Stra8-Cre (Mof cKO) caused global loss of H4K16ac. In leptotene and zygotene spermatocytes of cKO mice, the γH2AX signals were observed only along the chromosomal axes, and chromatin-wide H2AX phosphorylation was lost. In almost 40% of early-mid pachytene spermatocytes from Mof cKO mice, γH2AX and MDC1 were detected along the unsynapsed axes of the sex chromosomes, but failed to expand, which consequently caused meiotic sex chromosome inactivation (MSCI) failure. Furthermore, though RAD51 was proficiently recruited to double-strand break (DSB) sites, defects in DSB repair and crossover formation were observed in Mof cKO spermatocytes, indicating that MOF facilitates meiotic DSB repair after RAD51 recruitment. We propose that MOF regulates male meiosis and is involved in the expansion of all three waves of H2AX phosphorylation from the leptotene to pachytene stages, initiated by ATM and ATR, respectively. Phosphorylation of H2AX is a well-established step in the DNA damage response of somatic cells, and also occurs in germ cells during meiosis. During spermatogenesis, H2AX phosphorylation regulates the formation and repair of programmed DSBs and meiotic silencing of unpaired chromosomes. A critical step in these processes is spreading of H2AX phosphorylation along the chromosomes beyond the initiation site, which occurs by a poorly characterized mechanism. Here, we report that MOF is involved in the proper expansion of H2AX phosphorylation during meiosis. MOF also influences meiotic sex chromosome inactivation by facilitating early pachytene recruitment of MDC1, but is dispensable for BRCA1 or ATR recruitment to axial elements. Furthermore, MOF is involved in proper meiotic recombination and male germ cell development. As well as identifying a new MOF-dependent step for regulating expansion of H2AX phosphorylation, these findings have broad implications for the role of epigenetic modifications in meiosis and human reproductive health.
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作者：
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通讯作者：
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