Meiosis-specific ZFP541 repressor complex promotes meiotic prophase exit during spermatogenesis

Abstract

SummaryDuring spermatogenesis, meiosis is accompanied by robust alteration in gene expression and chromatin status. However, it remained elusive how meiotic transcriptional program is established to ensure completion of meiotic prophase. Here, we identified a novel protein complex consisting of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulator for meiotic prophase exit. Our genetic study showed that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses revealed that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrated that germ-cell specific ZFP541-KCTD19 containing complex promotes meiotic prophase exit in males, and triggers reconstruction of the transcription network and chromatin organization leading to post-meiotic development.

ZFP541 is indispensable for pachytene progression by interacting with KCTD19 and activates meiotic gene expression in mouse spermatogenesis

“…To elucidate the in vivo functions of Zfp541 , we used the CRISPR/Cas9 strategy to generate a Zfp541 knockout mouse model by targeted deletion of exon 3, and successfully confirmed the inactivation of this gene at the genome, mRNA transcription, as well as protein expression levels ( Figure 2-figure supplement 1 A-D ). Although developed normally, Zfp541 -/- males were sterile, in agreement with previous studies (Horisawa-Takada et al, 2021; Oura et al, 2021). The testes, the testis to body weight ratio and the seminiferous tubule diameter were all significantly smaller in the adult Zfp541 -/- males than Zfp541 +/- males ( Figure 2-figure supplement 1 E-G ).…”

“…KCTD19 associates with ZFP541 and HDAC1 and is required for meiotic exit in male mice (Horisawa-Takada et al, 2021; Oura et al, 2021). We wonder if KCTD19 is also vital for spermatogenesis, so we explored the expression pattern of KCTD19.…”

“…Horisawa-Takada et al . (2021) reported that HDAC1/2-containing ZFP541 complex directly represses the transcription of a subset of critical genes (Horisawa-Takada et al, 2021).…”

“…Horisawa-Takada et al . (2021) reported that HDAC1/2-containing ZFP541 complex directly represses the transcription of a subset of critical genes (Horisawa-Takada et al, 2021). HDAC1/2 complex is conventionally thought of as a genome-wide transcriptional repressor via histone deacetylation (Hassig et al, 1997; Kadosh and Struhl, 1998; Lee et al, 2018; Xue et al, 1998).…”

“…(2021) and Horisawa-Takada et al . (2021) have reported that the ZFP541/KCTD19 complex is indispensable for male meiosis and fertility (Horisawa-Takada et al, 2021; Oura et al, 2021). However, the specific role and the identity of its genome-wide target genes in the pachytene progression remain controversial.…”