H2A.Z deposition at meiotic prophase I underlies homologous recombination and pachytene genome activation during male meiosis

Abstract

Accurate meiotic progression is important for gamete formation and the generation of genetic diversity. However, little is known about the identity of chromatin regulators that underlie mammalian meiosis in vivo. Here, we identify the multifaceted functions of the chromatin remodeler Znhit1 in governing meiosis. We observe a gradual increase in Znhit1 expression during the meiotic prophase. Znhit1 deficiency in spermatocytes results in arrested pachytene development, impaired DNA double-strand break repair, and defective homologous recombination. Single-cell RNA sequencing and transcriptome analysis reveal that Znhit1 loss downregulates the transcription of pachytene genome activation (PGA) genes globally. Chromatin immunoprecipitation data show that Znhit1 is needed for the incorporation of the histone variant H2A.Z into pachytene chromatin. Moreover, we find that H2A.Z cooperates with the transcription factor A-MYB to co-bind DNA elements and control enhancer activity. Our findings provide insights into the regulatory mechanisms governing meiotic progression and highlight Znhit1 as a critical regulator of meiotic recombination and PGA.