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

TY - JOUR

T1 - T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex

AU - Hertweck, Arnulf

AU - Evans, Catherine M.

AU - Eskandarpour, Malihe

AU - Lau, Jonathan C.H.

AU - Oleinika, Kristine

AU - Jackson, Ian

AU - Kelly, Audrey

AU - Ambrose, John

AU - Adamson, Peter

AU - Cousins, David J.

AU - Lavender, Paul

AU - Calder, Virginia L.

AU - Lord, Graham M.

AU - Jenner, Richard G.

PY - 2016/6/21

Y1 - 2016/6/21

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84975154592

U2 - 10.1016/j.celrep.2016.05.054

DO - 10.1016/j.celrep.2016.05.054

M3 - Article

SN - 2211-1247

VL - 15

SP - 2756

EP - 2770

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -