Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression
Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia as well as failure of meiotic double strand formation followed by arrest at meiotic prophase I and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds to promoters of genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain containing genes, synaptonemal complex genes, and DNA damage response genes. Through transcriptionally regulating the interaction of these meiosis-related genes, we argue that CHD8 contributes to meiotic double strand break formation and subsequent meiotic progression. Our study uncovers an essential role of CHD8 for the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I. Overall design: RNA-seq analysis in Thy1+ and c-Kit+ spermatogonia from mice at 10 dpp (triplicate; Chd8 Ctrl vs. CKO), ChIP-seq analysis with antibody to CHD8 in unsorted testicular cells from mice at 12 dpp (triplicate; WT) and in Thy1+ and c-Kit+ spermatogonia from mice at 10 dpp (duplicate; Chd8 Ctrl vs. CKO), ChIP-seq analysis with antibody to H3K4me3 in c-Kit+ spermatogonia from mice at 10 dpp (duplicate; Chd8 Ctrl vs. CKO).