PHB regulates meiotic recombination via JAK2-mediated histone modifications in spermatogenesis
| Autor: | Wen-Jing Tan-Tai, Hong Chen, Xiao-Hui Li, Mo-Fang Liu, Wai-Sum O, Patricia A. Martin-DeLeon, HJ Shi, Ling-Fei Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mitochondrial ROS
Male Cohesin complex AcademicSubjects/SCI00010 Cell Cycle Proteins macromolecular substances Biology Cell Line Histones 03 medical and health sciences Epigenome Mice 0302 clinical medicine Meiosis Spermatocytes Prohibitins Testis Genetics Histone code Animals Prohibitin Phosphorylation Homologous Recombination Spermatogenesis Meiotic cohesin complex 030304 developmental biology Janus Kinases Mice Knockout 0303 health sciences Gene regulation Chromatin and Epigenetics technology industry and agriculture Janus Kinase 2 Cell biology Mitochondria Histone Code Repressor Proteins Chromosome Pairing STAT Transcription Factors Histone 030220 oncology & carcinogenesis Infertility biology.protein lipids (amino acids peptides and proteins) Pachytene Stage Signal Transduction |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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