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T-bet activates poised Th1 genes through Mediator and the Super Elongation Complex [ChIP-Seq]

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 super-enhancers in human and mouse Th1 cells to recruit Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1-specific genes are poised 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 super-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, but T-bet- and NF-κB-mediated pathways converge to allow P-TEFb recruitment. These data support a model in which lineage-specifying factors allow recruitment of P-TEFb to poised genes to promote differentiation of alternative T cell fates.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE62482 | GEO | 2016/06/08

SECONDARY ACCESSION(S): PRJNA264228

REPOSITORIES: GEO

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T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (Agilent 2)

Project description:The transcription factor T-bet induces differentiation of CD4+ T cells into the Th1 lineage and also allows for a degree of functional plasticity. Here, we show that T-bet acts through super-enhancers to recruit the elongation factor P-TEFb. Th1-specific genes are poised for activation in Th2 cells and P-TEFb recruitment activates transcriptional elongation. T-bet also induces extensive P-TEFb binding at super-enhancers, where it acts to stimulate enhancer RNA transcription. P-TEFb inhibition selectively blocks activation of lineage-specific genes and reverses Th1-associated retinitis pathology. T-bet-mediated recruitment of P-TEFb to super-enhancers at otherwise poised genes provides a model for how lineage-specifying factors promote differentiation towards specific cell fates whilst maintaining a degree of functional plasticity. Transcriptional profiling of mouse Th1 and Th2 cells treated with JQ1, which inhibits P-TEFb recruitment, or the P-TEFb inhibitor Flavopiridol vs DMSO conrol treated cells. Goal was to identify genes which are sensitive to P-TEFb inhibition.

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T-bet activates poised Th1 genes through Mediator and the Super Elongation Complex [ChIP-Seq]

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