T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex

•Th1 genes and Th2 genes are associated with RNA pol II in the alternative lineage•T-bet acts to recruit Mediator and the SEC to activate Th1 genes and eRNAs•T-bet and NF-κB-dependent P-TEFb recruitment pathways converge at enhancers•P-TEFb inhibition silences T-bet target genes and abrogates uveitis in vivo

SummaryThe transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes, and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, with T-bet- and NF-κB-mediated pathways instead converging to allow P-TEFb recruitment. These data provide insight into the mechanism through which lineage-specifying factors promote differentiation of alternative T cell fates.

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