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Title: T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex
Authors: Hertweck, Arnulf
Evans, Catherine M.
Eskandarpour, Malihe
Lau, Jonathan C. H.
Oleinika, Kristine
Jackson, Ian
Kelly, Audrey
Ambrose, John
Adamson, Peter
Cousins, David J.
Lavender, Paul
Calder, Virginia L.
Lord, Graham M.
Jenner, Richard G.
First Published: 9-Jun-2016
Publisher: Elsevier (Cell Press)
Citation: Cell Reports, 2016, 15 (12), pp. 2756-2770
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.
DOI Link: 10.1016/j.celrep.2016.05.054
eISSN: 2211-1247
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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