P15 | PHB/JAK/H3Y41PH AXIS REGULATES MEIOTIC RECOMBINATION IN SPERMATOGENESIS

H. Chen¹, L. Zhang¹, W. Tan-Tai¹, M. Liu², H. Shi³, W. O⁴, P.A. Martin-DeLeon⁵ | ¹Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China; ²State Key Laboratory of Molecular Biology, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai, China; ³NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China; ⁴School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; ⁵Department of Biological Sciences, University of Delaware, Newark, USA

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 PhbcKO mouse. Loss of PHB in spermatocytes resulted in complete male infertility, associated with not only meiotic pachytene arrest, 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.