Eukaryotic gene expression is dynamically regulated through the interplay between histone modifications and chromatin remodeling, yet how these processes are coordinated remains incompletely understood. Here, we uncover IBD1 as a critical adaptor that bridges histone acetylation and SWR-mediated H2A.Z deposition. Mechanistically, IBD1's bromodomain recognizes histone acetylation, specifically H3K9/K14 di-acetylation, to recruit the SWR complex subunit ARP6, ensuring precise H2A.Z incorporation into chromatin. H3K9Q mutation and genetic disruption of IBD1, either by deletion or bromodomain mutation, significantly reduce H2A.Z occupancy at target loci. In contrast, disruption of IBD1 has little effect on H3K9/K14 acetylation levels, confirming the directional hierarchy of the acetylation-IBD1-H2A.Z regulatory axis. Intriguingly, perturbation of this axis, through IBD1 loss or bromodomain impairment, leads to widespread transcriptional upregulation, particularly at genes co-enriched for IBD1, H3K9/K14ac, and H2A.Z, with the strongest effects at hyperacetylated loci. This transcriptional imbalance coincides with reduced growth rates, underscoring the functional significance of IBD1-mediated H2A.Z deposition. Given that H2A.Z enrichment is classically correlated with transcriptional levels, this observation highlights a dual role for H2A.Z: sustaining basal transcription and constraining overactivation at highly active genes. Together, our findings define a novel regulatory mechanism in which IBD1 bridges acetyl-mark decoding with SWR-dependent H2A.Z deposition, establishing transcriptional homeostasis.
Zhang et al. (2026) studied this question.