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

Byeong Seong Ki, Sung Han Shim, Chanhyeok Park, Hyunjin Yoo, Hyeonwoo La, Ok Hee Lee, Youngjoo Kwon, David G. Skalnik, Yuki Okada, Ho Geun Yoon, Jin Hoi Kim, Kwonho Hong, Youngsok Choi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1098-1108
Number of pages11
JournalExperimental and Molecular Medicine
Volume54
Issue number8
DOIs
StatePublished - Aug 2022

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