Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination.
Transcriptional regulatory networks direct the development of specialized cell types. The transcription factors signal tranducer and activator of transcription 4 (Stat4) and T-bet are required for the interleukin-12 (IL-12)-stimulated development of T helper 1 (Th1) cells, although the hierarchy of activity by these factors has not been clearly defined. In this report, we show that these factors did not function in a linear pathway and that each factor played a unique role in programming chromatin architecture for Th1 gene expression, with subsets of genes depending on Stat4, T-bet, or both for expression in Th1 cells. T-bet was not able to transactivate expression of Stat4-dependent genes in the absence of endogenous Stat4 expression. Thus, T-bet requires Stat4 to achieve complete IL-12-dependent Th1 cell-fate determination. These data provide a basis for understanding how transiently activated and lineage-specific transcription factors cooperate in promoting cellular differentiation.
Thieu
Vivian T
VT
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Yu
Qing
Q
Chang
Hua-Chen
HC
Yeh
Norman
N
Nguyen
Evelyn T
ET
Sehra
Sarita
S
Kaplan
Mark H
MH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000302:isolation & purification; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D000098815:T-bet Transcription Factor
D002843:Chromatin; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma