E-GEOD-40623 - Genome-wide regulatory analysis reveals T-bet controls Th17 lineage differentiation through direct suppression of IRF4
Released on 3 December 2013, last updated on 12 December 2013
The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells. ChIP-seq analysis of T-bet in WT and Tbet -/- mice.
Aditi Kanhere <email@example.com>, Graham Lord, M R Gökmen, Richard Jenner
Genome-Wide Regulatory Analysis Reveals That T-bet Controls Th17 Lineage Differentiation through Direct Suppression of IRF4. Gï¿½kmen MR, Dong R, Kanhere A, Powell N, Perucha E, Jackson I, Howard JK, Hernandez-Fuentes M, Jenner RG, Lord GM. , Europe PMC 24249732