H3K9 trimethylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that in male meiosis, ATF7IP2 amasses on autosomal and X-pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X-pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase I. Analyses of ATF7IP2-deficient meiosis reveal the protein's essential roles in the maintenance of MSCI, suppression of retrotransposons, and global up-regulation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition.

中文翻译：

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ATF7IP2/MCAF2 指导雄性种系中 H3K9 甲基化和减数分裂基因调控

H3K9 三甲基化 (H3K9me3) 在基因调控中发挥着新兴作用，其作用超出了其在中心周组成型异染色质上的积累。 H3K9me3 在雄性减数分裂中为何以及如何经历动态调节仍然是一个谜。在这里，我们确定了 H3K9 甲基化和生精异染色质组织的新型关键调节因子：种系特异性蛋白 ATF7IP2 (MCAF2)。我们发现，在雄性减数分裂中，ATF7IP2 积聚在常染色体和 X 中心异染色质上，扩散到整个性染色体，并积聚在数千个常染色体启动子和逆转录转座子基因座上。在经历减数分裂性染色体失活 (MSCI) 的性染色体上，DNA 损伤反应途径将 ATF7IP2 招募到 X 中心周异染色质，在那里它促进了 SETDB1（一种催化 H3K9me3 的组蛋白甲基转移酶）的招募。在缺乏 ATF7IP2 的情况下，雄性生殖细胞停滞在减数分裂前期 I。对 ATF7IP2 缺陷减数分裂的分析揭示了该蛋白在维持 MSCI、抑制逆转录转座子和常染色体基因整体上调中的重要作用。我们认为 ATF7IP2 是减数分裂中 DDR 途径的下游效应子，通过 SETDB1 介导的 H3K9me3 沉积的空间调控来协调异染色质的组织和基因调控。