The histone H3 lysine 36 demethylase KDM2A/FBXL11 controls Polycomb-mediated gene repression and germ cell development in male mice

Abstract

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters in Kdm2a-deficient spermatogonia. KDM2A is required for Polycomb-mediated repression as shown by increased H3K36me2 and reduced H3K27me3 promoter occupancies and failed gene repression in Kdm2a deficient differentiating spermatogonia. Loss of Kdm2a in spermatocytes disrupts progression through meiotic prophase, as evidenced by impaired completion of chromosome synapsis and processing of meiotic double-strand breaks (DSBs), by altered chromatin states and by an impairment of X-linked gene repression. Our study thus identifies critical roles for KDM2A in coordinating gene expression programs during spermatogonial differentiation and meiosis, which are essential for male germ cell development.