Integrated epigenome and transcriptome analysis of normal and arrested meiotic initiation during mouse spermatogenesis

The transition from mitotic to meiotic cell cycles is a transcriptional event that entails the activation of genes important for meiosis and requires germline-specific retinoic acid (RA) signaling target, Stra8. To identify novel transcription factors underlying mammalian meiotic initiation, we conducted integrative snATAC-seq and scRNA-seq analysis using wild-type and Stra8-deficient mouse testicular cells to map the chromatin accessibility and gene expression landscapes of normal and genetically arrested meiotic initiation. Our results identified a cluster of putative inhibitory transcription factors for meiotic initiation, which we consider "meiotic inhibitors". STRA8 binds to the regulatory sequences of these meiotic inhibitors and represses their expression upon meiotic initiation. In Stra8-deficient cells that suffer meiotic initiation arrest, the chromatin accessibility of these meiotic inhibitors is increased, concurrent with their uncontrolled and sustained expression. Among these meiotic inhibitors include KLF4, MAX, and MAZ. Importantly, by analyzing the single cell transcriptomes of human testes, our data show that these putative meiotic inhibitor genes are upregulated in early germ cells from patients with spermatogenic failure. Our study suggests that proper repression of meiotic inhibitors is essential for both mouse and human spermatogenesis.