Epigenetic regulator Cfp1 safeguards male meiotic progression by regulating meiotic gene expression

Abstract

Meiosis occurs specifically in germ cells to produce sperm and oocytes that are competent for sexual reproduction. Multiple factors are required for successful meiotic entry, progression, and termination. Among them, trimethylation of histone H3 on lysine 4 (H3K4me3), a mark of active transcription, has been implicated in spermatogenesis by forming double-strand breaks (DSBs). However, the role of H3K4me in transcriptional regulation during meiosis remains poorly understood. Here, we reveal that mouse CXXC finger protein 1 (Cfp1), a component of the H3K4 methyltransferase Setd1a/b, is dynamically expressed in differentiating male germ cells and safeguards meiosis by controlling gene expression. Genetic ablation of mouse CFP1 in male germ cells caused complete infertility with failure in prophase I of the 1st meiosis. Mechanistically, CFP1 binds to genes essential for spermatogenesis, and its loss leads to a reduction in H3K4me3 levels and gene expression. Importantly, CFP1 is highly enriched within the promoter/TSS of target genes to elevate H3K4me3 levels and gene expression at the pachytene stage of meiotic prophase I. The most enriched genes were associated with meiosis and homologous recombination during the differentiation of spermatocytes to round spermatids. Therefore, our study establishes a mechanistic link between CFP1-mediated transcriptional control and meiotic progression and might provide an unprecedented genetic basis for understanding human sterility.

Male fertility: Regulatory protein’s role in making sperm

Details of the role of a protein in the development of sperm cells in mice could lead to new understanding of sterility in men. An international research team led by Youngsok Choi and Kwonho Hong at Konkuk University, Seoul, South Korea, investigated the role of protein Cfp1, which they found to be required for sperm formation in mice. The protein is a component of an enzyme complex that transfers methyl groups (CH₃) onto other proteins involved in controlling gene activity. The researchers identified key aspects of the mechanism by which Cfp1 controls the activity of genes essential for sperm formation to proceed normally. Absence of Cfp1 specifically interferes with the process of meiosis, which generates sperm cells containing only one copy of each chromosome instead of the two copies found in other cells.