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 - http://www.scopus.com/inward/record.url?scp=84975154592&partnerID=8YFLogxK
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 -