SETDB1 Links the Meiotic DNA Damage Response to Sex Chromosome Silencing in Mice

Takayuki Hirota, P. Blakeley, M.N. Sangrithi, S.K. Mahadevaiah, V. Encheva, A.P. Snijders, E. ElInati, O.A. Ojarikre, D.G. de Rooij, K.K. Niakan, J.M.A. Turner

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article numberPMID: 30393076
Pages (from-to)645-659
Number of pages14
JournalDevelopmental Cell
Volume47
Issue number47 (5)
DOIs
Publication statusPublished - 2018

Keywords

  • meiotic silencing
  • MSCI
  • sex chromosomes
  • DNA damage response
  • mouse
  • H3K9me3

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