Department of Genetics, and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA.
Department of Genetics, and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA
Development. 2019 Jul 5;146(19):dev174094. doi: 10.1242/dev.174094.
A deficiency in BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, results in a meiotic arrest during spermatogenesis. Here, we explore the causative mechanisms. BRG1 is preferentially enriched at active promoters of genes essential for spermatogonial pluripotency and meiosis. In contrast, BRG1 is also associated with the repression of somatic genes. Chromatin accessibility at these target promoters is dependent upon BRG1. These results favor a model in which BRG1 coordinates spermatogenic transcription to ensure meiotic progression. In spermatocytes, BRG1 interacts with SCML2, a testis-specific PRC1 factor that is associated with the repression of somatic genes. We present evidence to suggest that BRG1 and SCML2 concordantly regulate genes during meiosis. Furthermore, BRG1 is required for the proper localization of SCML2 and its associated deubiquitylase, USP7, to the sex chromosomes during pachynema. SCML2-associated mono-ubiquitylation of histone H2A lysine 119 (H2AK119ub1) and acetylation of histone lysine 27 (H3K27ac) are elevated in testes. Coincidentally, the PRC1 ubiquitin ligase RNF2 is activated while a histone H2A/H2B deubiquitylase USP3 is repressed. Thus, BRG1 impacts the male epigenome by influencing the localization and expression of epigenetic modifiers. This mechanism highlights a novel paradigm of cooperativity between SWI/SNF and PRC1.
BRG1（SWI/SNF 染色质重塑复合物的催化亚基）的缺乏会导致精子发生过程中的减数分裂停滞。在这里，我们探索其致病机制。BRG1 优先富集在精原细胞多能性和减数分裂所必需的基因的活跃启动子处。相比之下，BRG1 也与体细胞基因的抑制有关。这些靶启动子处的染色质可及性依赖于 BRG1。这些结果支持了一个模型，即 BRG1 协调精子发生转录以确保减数分裂的进行。在精母细胞中，BRG1 与 SCML2 相互作用，后者是一种睾丸特异性 PRC1 因子，与体细胞基因的抑制有关。我们提供的证据表明，BRG1 和 SCML2 在减数分裂过程中协同调节基因。此外，BRG1 对于 SCML2 及其相关去泛素酶 USP7 在粗线期向性染色体的正确定位是必需的。SCML2 相关的组蛋白 H2A 赖氨酸 119（H2AK119ub1）单泛素化和组蛋白赖氨酸 27（H3K27ac）乙酰化在睾丸中升高。巧合的是，PRC1 泛素连接酶 RNF2 被激活，而组蛋白 H2A/H2B 去泛素酶 USP3 被抑制。因此，BRG1 通过影响表观遗传修饰物的定位和表达来影响雄性表观基因组。这种机制突出了 SWI/SNF 和 PRC1 之间协同作用的新范例。
