Hertweck, A;
Evans, CM;
Eskandarpour, M;
Lau, JC;
Oleinika, K;
Jackson, I;
Kelly, A;
... Jenner, RG; + view all
(2016)
T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.
Cell Reports
, 15
(12)
pp. 2756-2770.
10.1016/j.celrep.2016.05.054.
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Hertweck et al 2016 T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.pdf Download (5MB) | Preview |
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.
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