An H2A.Z-dependent epigenetic checkpoint in macrophages couples genetic risk to microbial metabolite signaling.

Abstract

Inflammatory gene programs must be precisely controlled to maintain immune homeostasis, yet the chromatin mechanisms enforcing transcriptional shutdown remain unclear. Here we show that the histone variant H2A.Z is evicted from pro-inflammatory loci upon acute macrophage activation and re-deposited during resolution. Myeloid-specific H2a.z deletion in mice causes unrestrained inflammatory transcription, arrested macrophage maturation, exacerbates colitis and dysbiosis, depleting butyrate-producing bacteria. Consistently, gut short-chain fatty acids, particularly butyrate, promote H2A.Z deposition through histone acylation, and butyrate's anti-inflammatory effects require H2A.Z. Strikingly, human inflammatory bowel disease (IBD)-associated risk variants are linked to reduced expression of GAS41 and TIP60, which form a reader-writer module that senses acylation mark to direct H2A.Z deposition. Diminished GAS41/TIP60 expression in patient tissues correlates with IBD progression and poor response to anti-TNF therapy. Thus, H2A.Z deposition functions as an acylation-dependent epigenetic checkpoint that couples macrophage differentiation to inflammatory resolution, integrating host genetics and microbial metabolites to calibrate immune responses.