KCTD19 and its associated protein ZFP541 are independently essential for meiosis in male mice.
KCTD19 and its associated protein ZFP541 are independently essential for meiosis in male mice.
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DOI：
10.1371/journal.pgen.1009412
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发表时间：
2021-05
期刊：
影响因子：
4.5
通讯作者：
Ikawa M
中科院分区：
文献类型：
--
作者：
Oura S;Koyano T;Kodera C;Horisawa-Takada Y;Matsuyama M;Ishiguro KI;Ikawa M
减数分裂是一个具有复杂染色体事件的细胞分裂过程，其中各种分子必须协同工作。为了寻找减数分裂相关基因，我们利用CRISPR/Cas9系统筛选了进化上保守且生殖道富集的基因，并鉴定了含有19（Kctd19）的钾通道四聚化结构域作为减数分裂的必需因子。在前期 I，Kctd19 缺陷不会影响突触或 DNA 损伤反应，并且在 Kctd19 KO 小鼠的中期 I 精母细胞中也观察到交叉结构。然而，精母细胞在中期-后期转变期间经历了凋亡消除。我们能够使用表位标记的 Kctd19 转基因来拯救 Kctd19 KO 表型。通过免疫沉淀-质谱法，我们证实了 KCTD19 与锌指蛋白 541 (ZFP541) 和组蛋白脱乙酰酶 1 (HDAC1) 的关联。 Zfp541 KO 精母细胞的表型分析表明，粗线期晚期存在 XY 染色体突联和反复出现的 DNA 损伤，导致细胞凋亡。总之，我们的研究表明 KCTD19 与 ZFP541 和 HDAC1 相关，并且 KCTD19 和 ZFP541 对于雄性小鼠的减数分裂至关重要。减数分裂是一个基本过程，包括一轮基因组 DNA 复制和两轮染色体分离，产生四个单倍体细胞。为了正确分配其遗传物质，细胞需要经历复杂的染色体事件，例如同源染色体的物理连接（称为突触）和减数分裂重组。参与这些事件的分子尚未完全表征，特别是在哺乳动物中。使用 CRISPR/Cas9 筛选系统，我们鉴定出含有 19 (Kctd19) 的钾通道四聚化结构域是雄性小鼠减数分裂的重要因子。此外，我们证实了 KCTD19 与锌指蛋白 541 (ZFP541) 和组蛋白脱乙酰酶 1 (HDAC1) 的关联。通过观察Zfp541敲除生殖细胞的减数分裂，我们发现Zfp541对于减数分裂也是必需的。这些结果表明KCTD19/ZFP541复合物起着关键作用，对于雄性减数分裂和生育能力是不可或缺的。
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. By immunoprecipitation-mass spectrometry, we confirmed the association of KCTD19 with zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1). 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 are essential for meiosis in male mice. Meiosis is a fundamental process that consists 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 confirmed the association of KCTD19 with zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1). By observing meiosis of Zfp541 knockout germ cells, we found that Zfp541 was also essential for meiosis. These results show that the KCTD19/ZFP541 complex plays a critical role and is indispensable for male meiosis and fertility.
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