KCTD19 associates with ZFP541 and HDAC1 and is required for meiotic exit in male mice

Abstract

Meiosis is a cell division process with complex chromosome events where various molecules must work in tandem. To find meiosis-related genes, we screened evolutionarily conserved and reproductive tract-enriched genes using the CRISPR/Cas9 system and identified potassium channel tetramerization domain containing 19 ( Kctd19 ) as an essential factor for meiosis. In prophase I, Kctd19 deficiency did not affect synapsis or the DNA damage response, and chiasma structures were also observed in metaphase I spermatocytes of Kctd19 KO mice. However, spermatocytes underwent apoptotic elimination during the metaphase-anaphase transition. We were able to rescue the Kctd19 KO phenotype with an epitope-tagged Kctd19 transgene. Immunoprecipitation-mass spectrometry identified zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1) as binding partners of KCTD19, indicating that KCTD19 is involved in chromatin modification. Phenotyping of Zfp541 KO spermatocytes demonstrated XY chromosome asynapsis and recurrent DNA damage in the late pachytene stage, leading to apoptosis. In summary, our study reveals that KCTD19 associates with ZFP541 and HDAC1, and that both KCTD19 and ZFP541 were essential for meiotic exit in male mice.

The testis-specific transcription factor TCFL5 responds to A-MYB to elaborate the male meiotic program in placental mammals

“…Our data, together with those from previous studies 5,11,23,30,45 , suggest a model for the evolutionarily conserved transcriptional architecture by which A-MYB and TCFL5 collaborate to reprogram gene expression at the onset of male meiosis I (Fig. 7).…”

“…Finally, the set of promoters bound by TCFL5 includes Kctd19 (Fig. 4e), a gene whose protein product is essential for meiotic exit 45 . The Kctd19 promoter is also bound by A-MYB.…”

“…Right panels, same as in the center panels, except comparing A-MYB and TCFL5 occupancy for the promoters of pachytene piRNA genes with or without conserved synteny among eutherian mammals. p-value was calculated using a twosided Mann-Whitney-Wilcoxon U test.Ozata et al, Extended Data Figure6Pachytene piRNA genes only in mouse(34) or with conserved synteny in murine rodents(45) or eutheria(21) Spearman correlation for histone modification, BTBD18 binding, or CG content (rpm) versus TF occupancy (rpm)…”