Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
Yale Stem Cell Center, New Haven, CT 06510, USA.
Development. 2023 May 1;150(9). doi: 10.1242/dev.201497. Epub 2023 May 12.
Unique chromatin remodeling factors orchestrate dramatic changes in nuclear morphology during differentiation of the mature sperm head. A crucial step in this process is histone-to-protamine exchange, which must be executed correctly to avoid sperm DNA damage, embryonic lethality and male sterility. Here, we define an essential role for the histone methyltransferase DOT1L in the histone-to-protamine transition. We show that DOT1L is abundantly expressed in mouse meiotic and postmeiotic germ cells, and that methylation of histone H3 lysine 79 (H3K79), the modification catalyzed by DOT1L, is enriched in developing spermatids in the initial stages of histone replacement. Elongating spermatids lacking DOT1L fail to fully replace histones and exhibit aberrant protamine recruitment, resulting in deformed sperm heads and male sterility. Loss of DOT1L results in transcriptional dysregulation coinciding with the onset of histone replacement and affecting genes required for histone-to-protamine exchange. DOT1L also deposits H3K79me2 and promotes accumulation of elongating RNA Polymerase II at the testis-specific bromodomain gene Brdt. Together, our results indicate that DOT1L is an important mediator of transcription during spermatid differentiation and an indispensable regulator of male fertility.
独特的染色质重塑因子在成熟精子头的分化过程中协调核形态的剧烈变化。这个过程中的一个关键步骤是组蛋白到鱼精蛋白的交换，必须正确执行，以避免精子 DNA 损伤、胚胎致死和雄性不育。在这里，我们定义了组蛋白甲基转移酶 DOT1L 在组蛋白到鱼精蛋白转换中的重要作用。我们表明，DOT1L 在小鼠减数分裂和减数分裂后生殖细胞中大量表达，并且由 DOT1L 催化的组蛋白 H3 赖氨酸 79（H3K79）的甲基化在初始阶段的组蛋白替换中丰富存在于发育中的精原细胞中。缺乏 DOT1L 的伸长精原细胞不能完全替换组蛋白，并表现出异常的鱼精蛋白募集，导致精子头变形和雄性不育。DOT1L 的缺失导致转录失调，与组蛋白替换的开始同时发生，并影响组蛋白到鱼精蛋白交换所需的基因。DOT1L 还沉积 H3K79me2 并促进延长的 RNA 聚合酶 II 在睾丸特异性溴结构域基因 Brdt 处的积累。总之，我们的结果表明，DOT1L 是精子细胞分化过程中转录的重要介质，也是雄性生育力不可或缺的调节剂。
