Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
Biol Reprod. 2024 Feb 10;110(2):391-407. doi: 10.1093/biolre/ioad141.
Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild-type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias toward downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.
父本染色质在哺乳动物精子发生过程中经历广泛的结构和表观遗传改变，产生的精子具有优化的表观基因组，以适应胚胎发生的转变。赖氨酸去甲基酶 6a（KDM6A，也称为 UTX）通过去甲基化 H3K27me3 促进基因激活，H3K27me3 是一种发育过程中重要的抑制性修饰，在精子发生细胞和精子的整个表观基因组中都很丰富。我们之前的研究表明，源自缺乏 Kdm6a 的父本生殖系的遗传野生型小鼠患癌症的风险增加（Kdm6a cKO），表明 KDM6A 在调节可遗传的表观遗传状态中发挥作用。然而，KDM6A 在精子发生过程中的调节功能尚不清楚。在这里，我们表明 Kdm6a 在精子发生过程中短暂表达，RNA 和蛋白质表达主要局限于晚期精原细胞和早期减数分裂前期。Kdm6a cKO 雄性在生育能力或精子发生的整体进展方面没有缺陷。然而，在精子发生细胞中失去 Kdm6a 时，数百个基因被下调，这种下调与 Kdm6a 表达的时间强烈相关。失调的基因编码参与染色质组织和重复元件调节的因子，其中一些基因在 Kdm6a cKO 雄性的两个世代的后代的雄性生殖系中持续失调。全基因组表观遗传分析显示，Kdm6a cKO 小鼠分化的精原细胞中 H3K27me3 峰变宽，表明 KDM6A 在雄性生殖系中划定 H3K27me3 结构域。我们的研究结果强调了 KDM6A 作为哺乳动物雄性生殖系中的转录激活因子的作用，它对于精子发生是可有可无的，但对于保障基因调控状态的代际传递是重要的。
