Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli.
Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and corecruitment of STAT4. STAT4 and NF-kappaB therefore cooperate at multiple cis elements to enable NF-kappaB-dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in T helper 1 (Th1) and effector CD8(+) T (Tc1) cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals.
Balasubramani
Anand
A
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Shibata
Yoichiro
Y
Crawford
Gregory E
GE
Baldwin
Albert S
AS
Hatton
Robin D
RD
Weaver
Casey T
CT
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation; D000098815:T-bet Transcription Factor
D020382:Interleukin-18; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051996:Transcription Factor RelA; D018664:Interleukin-12; D007371:Interferon-gamma