Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function.
A transcription factor network that includes STAT4, T-bet, and Runx3 promotes the differentiation of Th1 cells and inflammatory immune responses. How additional transcription factors regulate the function of Th1 cells has not been defined. In this study we show that the negative regulatory factor Twist1 decreases expression of T-bet, Runx3, and IL-12Rβ2 as it inhibits IFN-γ production. Ectopic expression of Runx3, but not T-bet or IL-12Rβ2, compensates for the effects of Twist1 on IFN-γ production, and Twist1 regulation of Ifng depends on complex formation with Runx3. Twist1 decreases Runx3 and T-bet binding at the Ifng locus, and it decreases chromatin looping within the Ifng locus. These data define an IL-12/STAT4-induced negative regulatory loop that impacts multiple components of the Th1 transcriptional network and provide further insight into regulation of Th1 differentiation.
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Duy
D
Pham
Joshua W
JW
Vincentz
Anthony B
AB
Firulli
Mark H
MH
Kaplan
D000818:Animals; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000502:physiology*; D000098815:T-bet Transcription Factor
D050677:Core Binding Factor Alpha 3 Subunit; D009687:Nuclear Proteins; C493730:Runx3 protein, mouse; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D007371:Interferon-gamma