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

Dev Cell. 2018 Dec 3;47(5):645-659.e6. doi: 10.1016/j.devcel.2018.10.004. Epub 2018 Nov 1.

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.

Keywords: DNA damage response; H3K9me3; MSCI; meiotic silencing; mouse; sex chromosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Chromosome Pairing*
  • DNA Damage*
  • DNA Repair
  • Gene Silencing*
  • Histone Code*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Tripartite Motif-Containing Protein 28 / genetics
  • Tripartite Motif-Containing Protein 28 / metabolism

Substances

  • Histones
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, mouse
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28