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

Arnulf Hertweck, Catherine M. Evans, Malihe Eskandarpour, Jonathan C.H. Lau, Kristine Oleinika, Ian Jackson, Audrey Kelly, John Ambrose, Peter Adamson, David J. Cousins, Paul Lavender, Virginia L. Calder, Graham M. Lord, Richard G. Jenner

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    Abstract

    The 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.
    Original languageEnglish
    Pages (from-to)2756–2770
    JournalCell Reports
    Volume15
    Issue number12
    Early online date9 Jun 2016
    DOIs
    Publication statusPublished - 21 Jun 2016

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