Sex Chromosome Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Dev Cell. 2018 Dec 3;47(5):645-659.e6. doi: 10.1016/j.devcel.2018.10.004. Epub 2018 Nov 1.
Meiotic synapsis and recombination ensure correct homologous segregation and genetic diversity. Asynapsed homologs are transcriptionally inactivated by meiotic silencing, which serves a surveillance function and in males drives meiotic sex chromosome inactivation. Silencing depends on the DNA damage response (DDR) network, but how DDR proteins engage repressive chromatin marks is unknown. We identify the histone H3-lysine-9 methyltransferase SETDB1 as the bridge linking the DDR to silencing in male mice. At the onset of silencing, X chromosome H3K9 trimethylation (H3K9me3) enrichment is downstream of DDR factors. Without Setdb1, the X chromosome accrues DDR proteins but not H3K9me3. Consequently, sex chromosome remodeling and silencing fail, causing germ cell apoptosis. Our data implicate TRIM28 in linking the DDR to SETDB1 and uncover additional factors with putative meiotic XY-silencing functions. Furthermore, we show that SETDB1 imposes timely expression of meiotic and post-meiotic genes. Setdb1 thus unites the DDR network, asynapsis, and meiotic chromosome silencing.
减数分裂联会和重组确保同源染色体正确分离和遗传多样性。未联会的同源染色体通过减数分裂沉默转录失活，这种沉默具有监控功能，并在雄性中驱动减数分裂性染色体失活。沉默依赖于 DNA 损伤反应 (DDR) 网络，但 DDR 蛋白如何与抑制性染色质标记结合尚不清楚。我们鉴定出组蛋白 H3-赖氨酸-9 甲基转移酶 SETDB1 作为 DDR 与雄性小鼠沉默之间的桥梁。在沉默开始时，X 染色体 H3K9 三甲基化 (H3K9me3) 富集是 DDR 因子的下游事件。没有 Setdb1，X 染色体就会积累 DDR 蛋白，但不会积累 H3K9me3。因此，性染色体重塑和沉默失败，导致生殖细胞凋亡。我们的数据表明 TRIM28 将 DDR 与 SETDB1 联系起来，并揭示了具有潜在减数分裂 XY 沉默功能的其他因素。此外，我们还表明 SETDB1 会适时表达减数分裂和减数分裂后基因。因此，SETDB1 将 DDR 网络、联会和减数分裂染色体沉默结合在一起。
