The Meiotic Function For MOF In Male Mice

Meiosis is a specialized cell division during which germ cells undergo two rounds of cell division after a single round of DNA replication to generate haploid gametes.To ensure the proper segregation of homologous chromosomes during meiosis prophase I,a series of cytological events would take place.The special dynamic of the distribution of yH2AX is a key marker for meiotic progression.Three waves of spreading of H2AX phosphorylation have been observed in male meiotic prophase I.These waves of spreading of H2AX phosphorylation included the spreading of DSB-independent H2AX phosphorylation mediated by ATM to the whole nucleus in leptotene;The spreading of DSB-dependent H2AX phosphorylation mediated by ATR to the whole nucleus in zygotene and the spreading of ATR dependent H2AX phosphorylation marking the unsynapsed axes to the chromatin-wide region of sex-body after pachytene stage.However,little is known about how H2AX phosphorylation spreads to chromatin-wide regions in spermatocytes.Here,we report that histone acetyltransferase(HAT)MOF participates in the all three waves of H2AX phosphorylation spreading.Specific deletion of Mof in spermatocytes by Stra8-Cre(Mof cKO)caused global loss of H4K16ac as well as male sterility.Spermatogenesis in most seminefous tubules arrested at the primary spermatocyte stage in Mof cKO mice.The YH2AX signals can only be found along the chromosomal axes,with the chromatin-wide H2AX phosphorylation completely lost in Mof cKO leptotene and zygotene spermatocytes.In 40%Mof cKO pachytene spermatocytes,YH2AX and MDC1 were detected along the axes of sex chromosomes,but failed to spread to the whole region of sex body as seen in cells from wild-type(WT)mice,which consequently causes MSCI failure.Furthermore,though RAD51 was proficiently recruited to DSB sites,defects on DSB repair and crossover formation were also observed in Mof cKO spermatocytes,indicating MOF facilitates meiotic DSB repair after RAD51 recruitment.These results indicate that MOF is indispensible for meiosis of male mice by facilitating the chromatin-wide spreading of the three waves of meiosis specific H2AX phosphorylation and DSB repair,and serve as the only known factor responsible for the all three waves of H2AX phosphorylation spreading from leptotene to pachytene stage initiated by ATM and ATR respectively.