PHB regulates meiotic recombination via JAK2-mediated histone modifications in spermatogenesis
PHB regulates meiotic recombination via JAK2-mediated histone modifications in spermatogenesis
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PHB 通过 JAK2 介导的精子发生中的组蛋白修饰来调节减数分裂重组。
DOI：
10.1093/nar/gkaa203
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发表时间：
2020-05-21
影响因子：
14.9
通讯作者：
Chen, Hong
中科院分区：
文献类型：
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作者：
Zhang, Ling-Fei;Tan-Tai, Wen-Jing;Chen, Hong
以前，我们已经表明，人精子抑制素（PHB）的表达与线粒体活性氧水平显着负相关，但与线粒体膜电位和运动呈正相关。然而，PHB在哺乳动物精子发生中的可能作用尚未研究。在这里，我们文件中的精母细胞及其功能作用的存在下，在减数分裂产生的第一个雄性生殖细胞特异性Phb-cKO小鼠。精母细胞中PHB的缺失导致完全男性不育，不仅与减数分裂粗线期阻滞伴随细胞凋亡有关，而且与线粒体形态和功能受损导致的细胞凋亡有关。我们的机制研究表明，在精母细胞中的PHB调节STAG 3的表达，一个关键组成部分的减数分裂cohesin复合物，通过一个非经典的JAK/STAT途径，从而促进减数分裂DSB修复和同源重组。此外，PHB/JAK 2轴被发现作为一种新的机制，在维持减数分裂的STAG 3凝聚素复合物的稳定性和调节异染色质的形成在精母细胞减数分裂。所观察到的JAK 2介导的组蛋白修饰的表观遗传变化，反映在组蛋白3酪氨酸41磷酸化（H3 Y 41 ph）的减少和H3 K9 me 3在Stag 3位点的保留，可能是导致精母细胞中的Stag 3失调与PHB的损失。
Previously, we have shown that human sperm Prohibitin (PHB) expression is significantly negatively correlated with mitochondrial ROS levels but positively correlated with mitochondrial membrane potential and motility. However, the possible role of PHB in mammalian spermatogenesis has not been investigated. Here we document the presence of PHB in spermatocytes and its functional roles in meiosis by generating the first male germ cell-specific Phb-cKO mouse. Loss of PHB in spermatocytes resulted in complete male infertility, associated with not only meiotic pachytene arrest with accompanying apoptosis, but also apoptosis resulting from mitochondrial morphology and function impairment. Our mechanistic studies show that PHB in spermatocytes regulates the expression of STAG3, a key component of the meiotic cohesin complex, via a non-canonical JAK/STAT pathway, and consequently promotes meiotic DSB repair and homologous recombination. Furthermore, the PHB/JAK2 axis was found as a novel mechanism in the maintenance of stabilization of meiotic STAG3 cohesin complex and the modulation of heterochromatin formation in spermatocytes during meiosis. The observed JAK2-mediated epigenetic changes in histone modifications, reflected in a reduction of histone 3 tyrosine 41 phosphorylation (H3Y41ph) and a retention of H3K9me3 at the Stag3 locus, could be responsible for Stag3 dysregulation in spermatocytes with the loss of PHB.