Abstract
SummaryMeiotic 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.
Highlights
Defective synapsis or recombination can cause mutation and aneuploidy in offspring
DNA damage response (DDR) Factors Direct H3K9me3 Acquisition on the X Chromosome at Pachynema Using SYCP3 immunostaining to label chromosome axial elements, we first confirmed previous reports (Kato et al, 2015; Page et al, 2012; van der Heijden et al, 2007; Khalil et al, 2004) that H3K9me3 is enriched on the XY bivalent, as well as on pericentric heterochromatin, at early pachynema (Figure 1B)
H3K9me3 was not observed along chromosome axes or at persistent meiotic double-strand breaks (DSBs) sites (Figure S1A)
Summary
Defective synapsis or recombination can cause mutation and aneuploidy in offspring. To prevent these outcomes, surveillance mechanisms operate during prophase I to eliminate germ cells in which either process is defective. The first is triggered by persistent DNA damage and transduces germ cell elimination via the CHK2/p53/p63 checkpoint pathway The second operates in the absence of persistent DNA damage and responds instead to asynapsis (Di Giacomo et al, 2005; Wojtasz et al, 2012). Homologs asynapsed at pachynema undergo meiotic silencing, a megabase-scale chromatin remodeling process that inactivates hundreds of genes (Inagaki et al, 2010). Evidence suggests that meiotic silencing eliminates germ cells with asynapsis by depriving them of critical gene products (Cloutier et al, 2015)
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