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Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology

ABSTRACT: T helper (Th) differentiation is regulated by diverse inputs including the Vitamin A metabolite retinoic acid (RA). RA acts through its receptor RAR to repress transcription of inflammatory cytokines, but it is also essential for Th-mediated immunity, pointing to complex effects of RA in Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during differentiation of CD4+ T cells to multiple Th subsets. RA effects were subset-selective, and quantitatively greatest in Th9 cells. RA globally antagonized Th9-promoting transcription factors (TFs) and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARa. RA-RARaactivity limited Th9-associated pulmonary inflammation in mice, and allergic inflammation in humans was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARa signaling in Th differentiation, arguing for a role for RA in IL-9 related diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE123501 | GEO | 2019/02/05

REPOSITORIES: GEO

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