H3.3 chaperone Hira primes the effector program and function of regulatory T cells [CUT&Tag]

While several transcription factors such as Batf, Irf4, JunB have been reported to be essential for eTreg differentiation and function, the underlying epigenetic mechanism remains unclear. Here, we show that the histone variant H3.3 is enriched in tissue Tregs compared to splenic Tregs and its chaperone Hira is a critical regulator of Treg effector program.

Treg specific-deletion of Hira resulted in reduced eTreg population, impaired suppressive function and multi-organ inflammation in mice. Mechanistically, Hira-dependent H3.3 deposition establishes a permissive epigenetic environment by enhancing chromatin accessibility, facilitating H3K36me3 and preventing H3K27me3 modifications on loci of genes enriched for AP-1 binding motif and associated with Treg effector function.