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Immunity. 2010 Jul 23;33(1):35-47. doi: 10.1016/j.immuni.2010.07.004.

Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli.

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1
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Abstract

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.

PMID:
20643337
PMCID:
PMC2994316
DOI:
10.1016/j.immuni.2010.07.004
[Indexed for MEDLINE]
Free PMC Article

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