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

• DOI: 10.1101/2021.02.12.430913
• Publication Date: 2021-02-13T07:30:29Z
• Authors: Seiya Oura; Takayuki Koyano; Chisato Kodera; Yuki Horisawa-Takada; Makoto Matsuyama; Kei-ichiro Ishiguro; Masahito Ikawa
• Keywords: 0301 basic medicine; 03 medical and health sciences

AbstractMeiosis 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,Kctd19deficiency did not affect synapsis or the DNA damage response, and chiasma structures were also observed in metaphase I spermatocytes ofKctd19KO mice. However, spermatocytes underwent apoptotic elimination during the metaphase-anaphase transition. We were able to rescue theKctd19KO phenotype with an epitope-taggedKctd19transgene. 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 ofZfp541KO 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.Author summaryMeiosis is a fundamental process that consisting of one round of genomic DNA replication and two rounds of chromosome segregation producing four haploid cells. To properly distribute their genetic material, cells need to undergo complex chromosome events such as a physical linkage of homologous chromosomes (termed synapsis) and meiotic recombination. The molecules involved in these events have not been fully characterized yet, especially in mammals. Using a CRISPR/Cas9-screening system, we identified the potassium channel tetramerization domain containing 19 (Kctd19) as an essential factor for meiosis in male mice. Further, we identified zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1) as binding partners of KCTD19. By observing meiosis ofZfp541knockout germ cells, we found thatZfp541was also essential for meiotic completion. These results show that the KCTD19/ZFP541 complex plays a critical role and is indispensable for male meiosis and fertility.