ZFP541 maintains the repression of pre-pachytene transcriptional programs and promotes male meiosis progression.

The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of the pachytene stage. However, the biological significance and underlying mechanisms remain largely unclear. Here, we report that ZFP541 is indispensable for the suppression of DSB formation after mid-pachytene. The deletion of Zfp541 in mice causes the aberrant recruitment of DSB machinery to chromosome axes and generation of massive DSBs in late pachytene and diplotene spermatocytes, leading to meiotic arrest at the diplotene stage. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data indicate that ZFP541 predominantly binds to promoters of pre-pachytene genes, including meiotic DSB formation-related genes (e.g., Prdm9 and Mei1) and their upstream activators (e.g., Meiosin and Rxra), and maintains their repression in pachytene spermatocytes. Our results reveal that ZFP541 functions as a transcriptional regulator in pachytene spermatocytes, orchestrating the transcriptome to ensure meiosis progression. [Display omitted] • ZFP541 deficiency in spermatocytes causes meiotic arrest at the diplotene stage • Zfp541 deletion causes aberrant DSB generation in spermatocytes after mid-pachytene • ZFP541 represses the expression of meiotic DSB formation genes in pachytene • ZFP541 binds promoters of pre-pachytene genes to maintain their repression in pachytene Xu et al. demonstrate that ZFP541 predominantly maintains the repression of pre-pachytene transcriptional programs, including meiotic DSB formation genes, in pachytene spermatocytes and suppresses aberrant DSB formation after mid-pachytene, thus ensuring meiosis progression. [ABSTRACT FROM AUTHOR]