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

Cell Rep. 2016 Jun 21;15(12):2756-70. doi: 10.1016/j.celrep.2016.05.054.

Arnulf Hertweck ¹, Catherine M Evans ², Malihe Eskandarpour ³, Jonathan C H Lau ², Kristine Oleinika ², Ian Jackson ⁴, Audrey Kelly ⁵, John Ambrose ², Peter Adamson ³, David J Cousins ⁶, Paul Lavender ⁵, Virginia L Calder ³, Graham M Lord ⁷, Richard G Jenner ⁸

Affiliations

1 UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK; Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK.
2 UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK.
3 UCL Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
4 Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK.
5 Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK.
6 Department of Asthma, Allergy, and Respiratory Science, King's College London, SE1 9RT London, UK; Leicester Institute for Lung Health and Department of Infection, Immunity, and Inflammation, NIHR Leicester Respiratory Biomedical Research Unit, University of Leicester, LE3 9QP Leicester, UK.
7 Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, SE1 9RT London, UK. Electronic address: graham.lord@kcl.ac.uk.
8 UCL Cancer Institute, University College London, 72 Huntley Street, W1T 4JF London, UK. Electronic address: r.jenner@ucl.ac.uk.

PMID: 27292648 DOI: 10.1016/j.celrep.2016.05.054

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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