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SETDB1 links the meiotic DNA damage response to sex chromosome silencing in mice
journal contributionposted on 2020-08-12, 11:42 authored by Takayuki Hirota, Paul Blakeley, Mahesh N Sangrithi, Shantha K Mahadevaiah, Vesela Encheva, Ambrosius P Snijders, Elias ElInati, Obah A Ojarikre, Dirk G de Rooij, Kathy K Niakan, James MA Turner
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.
DNA damage responseH3K9me3MSCImeiotic silencingmousesex chromosomesAnimalsApoptosisChromosome PairingDNA DamageDNA RepairGene SilencingHistone CodeHistone-Lysine N-MethyltransferaseHistonesMaleMiceMice, Inbred C57BLTripartite Motif-Containing Protein 28Turner FC001193Niakan FC001120PRTBRF-ackAS-ackLM-ackHP-ackDevelopmental Biology06 Biological Sciences11 Medical and Health Sciences