SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice.
SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice.
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DOI：
10.1016/j.devcel.2018.10.004
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发表时间：
2018-12-03
影响因子：
11.8
通讯作者：
Turner JMA
中科院分区：
文献类型：
--
作者：
Hirota T;Blakeley P;Sangrithi MN;Mahadevaiah SK;Encheva V;Snijders AP;ElInati E;Ojarikre OA;de Rooij DG;Niakan KK;Turner JMA
减数分裂联会和重组确保正确的同源分离和遗传多样性。无突触同源物通过减数分裂沉默而转录失活，减数分裂沉默起监视作用，并且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蛋白如何参与抑制性染色质标记尚不清楚。我们确定组蛋白H3-赖氨酸-9甲基转移酶SETDB 1作为连接雄性小鼠DDR沉默的桥梁。在沉默开始时，X染色体H3 K9三甲基化（H3 K9 me 3）富集是DDR因子的下游。如果没有Setdb 1，X染色体会产生DDR蛋白，但不会产生H3 K9 me 3。因此，性染色体重塑和沉默失败，导致生殖细胞凋亡。我们的数据暗示TRIM 28将DDR与SETDB 1联系起来，并揭示了具有推定的减数分裂XY沉默功能的其他因素。此外，我们表明，SETDB 1施加减数分裂和减数分裂后的基因的及时表达。因此，Setdb 1将DDR网络、不联会和减数分裂染色体沉默结合在一起。组蛋白甲基转移酶SETDB 1是雄性小鼠减数分裂所必需的。减数分裂DDR网络将SETDB 1招募到XY对，在XY对中它诱导H3 K9 me 3 SETDB 1缺失扰乱减数分裂性染色体重塑，并且沉默SETDB 1确保减数分裂和减数分裂后基因的及时表达。在哺乳动物的雄性减数分裂期间，X和Y染色体的不联会区域保留DNA双链断裂（DSB），从而引发性染色体的沉默，这是生育的一个重要过程。Hirota等人显示减数分裂DSB因子募集H3 K9-甲基转移酶SETDB 1，诱导XY-染色质重塑和沉默。
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. The histone methyltransferase SETDB1 is essential for male mouse meiosis The meiotic DDR network recruits SETDB1 to the XY pair, where it induces H3K9me3 SETDB1 deletion perturbs meiotic sex chromosome remodeling and silencing SETDB1 ensures timely expression of meiotic and post-meiotic genes During male meiosis in mammals, the asynapsed regions of the X and Y chromosomes retain DNA double-strand breaks (DSBs), which triggers silencing of the sex chromosomes, a process essential for fertility. Hirota et al. show that meiotic DSB factors recruit the H3K9-methyltransferase SETDB1, inducing XY-chromatin remodeling and silencing.
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影响因子：
16.8
作者：
Borensztein M;Syx L;Ancelin K;Diabangouaya P;Picard C;Liu T;Liang JB;Vassilev I;Galupa R;Servant N;Barillot E;Surani A;Chen CJ;Heard E
通讯作者：
Heard E
影响因子：
56.9
作者：
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通讯作者：
Nussenzweig, A
影响因子：
3.3
作者：
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通讯作者：
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影响因子：
2.7
作者：
Baarends, WM;Hoogerbrugge, TW;Grootegoed, JA
通讯作者：
Grootegoed, JA
影响因子：
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作者：
Baumann C;Schmidtmann A;Muegge K;De La Fuente R
通讯作者：
De La Fuente R