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PHB regulates meiotic recombination via JAK2-mediated histone modifications in spermatogenesis.
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2020-05-21 , DOI: 10.1093/nar/gkaa203
Ling-Fei Zhang 1 , Wen-Jing Tan-Tai 1 , Xiao-Hui Li 1 , Mo-Fang Liu 2 , Hui-Juan Shi 3 , Patricia A Martin-DeLeon 4 , Wai-Sum O 5 , Hong Chen 1
Affiliation  

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.

中文翻译:

PHB通过精子发生中JAK2介导的组蛋白修饰调节减数分裂重组。

以前,我们已经证明人类精子抑制素(PHB)的表达与线粒体ROS水平显着负相关,而与线粒体膜电位和运动性正相关。但是,尚未研究PHB在哺乳动物精子发生中的可能作用。在这里,我们通过生成第一只雄性生殖细胞特异性Phb-cKO小鼠,记录了精细胞中PHB的存在及其在减数分裂中的功能作用。精母细胞中PHB的丧失导致男性完全不育,不仅与减数分裂的粗线阻滞伴随着细胞凋亡有关,而且与线粒体形态和功能受损引起的细胞凋亡有关。我们的机理研究表明,精原细胞中的PHB调节STAG3的表达,STAG3是减数分裂粘附素复合物的关键成分,通过非规范的JAK / STAT途径,从而促进减数分裂DSB修复和同源重组。此外,发现PHB / JAK2轴是维持减数分裂STAG3黏着蛋白复合物稳定和减数分裂过程中精细胞异染色质形成调节的新机制。观察到的JAK2介导的组蛋白修饰的表观遗传学变化反映在组蛋白3酪氨酸41磷酸化(H3Y41ph)的减少和H3K9me3在Stag3位点的保留,可能是精子细胞Stag3失调的原因,PHB丢失。在减数分裂过程中,PHB / JAK2轴被认为是维持减数分裂STAG3黏附蛋白复合物稳定和调节精细胞异染色质形成的新机制。观察到的JAK2介导的组蛋白修饰的表观遗传学变化反映在组蛋白3酪氨酸41磷酸化(H3Y41ph)的减少和H3K9me3在Stag3位点的保留,可能是精子细胞Stag3失调的原因,PHB丢失。在减数分裂过程中,PHB / JAK2轴被认为是维持减数分裂STAG3黏附蛋白复合物稳定和调节精细胞异染色质形成的新机制。观察到的JAK2介导的组蛋白修饰的表观遗传学变化反映为组蛋白3酪氨酸41磷酸化(H3Y41ph)的减少和H3K9me3在Stag3位点的保留,这可能是精子细胞Stag3失调和PHB丢失的原因。
更新日期:2020-03-30
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