Competition for H2A.Z between genes and repetitive elements establishes response to anti-viral immune activation

Abstract

Activation of endogenous retroviruses leads to widespread transcriptional reprograming, affecting innate immune activation, metabolic control, and development. We find that the histone variant H2A.Z plays a central role in orchestrating these responses. Stimulating retroviral expression in zebrafish embryos causes H2A.Z to exit developmental gene promoters, which become silent, and to accumulate specifically at 'primed' repetitive elements, which are pre-marked by H3K27ac and H3K9me3. Remarkably, this rewiring is greatly influenced by total H2A.Z abundance, and developmental consequences of retrovirus activation are mitigated by H2A.Z over-expression. Our results uncover mechanisms whereby H2A.Z levels determine sensitivity to retroviral activation, and repetitive elements function as a nuclear sink to dramatically influence total transcriptional output.

The chromatin source-sink hypothesis: a shared mode of chromatin-mediated regulations

“…Recent studies of zebrafish have found that sensitivity to environmental factors may also depend on the availability of source factors relative the sink capacity. In developing zebrafish embryos, exposure to either a common flame retardant, Tris(1,3-dichloro-2-propyl)phosphate, or a DNA methylation inhibitor, 5-aza-deoxycytidine, causes H2A.Z to accumulate specifically at transcriptionally active repetitive elements, including DNA transposons and satellite repeats ( Meng et al, 2022 preprint). These changes coincide with loss of H2A.Z at promoter regions, leading to transcriptional downregulation of genes proximal to impacted loci.…”