Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Immunity. 2010 Jul 23;33(1):35-47. doi: 10.1016/j.immuni.2010.07.004.
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.
远端顺式调控元件在细胞因子基因的 T 细胞系特异性表达中发挥着重要作用。我们已经定位了三个反式作用因子-NF-κB、STAT4 和 T-bet-与 Ifng 基因座中的顺式元件的相互作用。我们发现 RelA 对于最佳 Ifng 表达是至关重要的，并且根据 T 细胞受体 (TCR) 或白细胞介素-12 (IL-12) 加白细胞介素-18 (IL-18) 信号的不同而被差异化招募到多个元件上。RelA 对至少四个元件的募集依赖于 T-bet 依赖性重塑 Ifng 基因座和 STAT4 的共募集。因此，STAT4 和 NF-κB 在多个顺式元件上合作，从而实现 NF-κB 依赖性增强 Ifng 表达。在 Th1 和效应 CD8(+) T (Tc1) 细胞中，RelA 对远端元件的募集是相似的，尽管 T-bet 在 CD8 效应器中是可有可无的。这些结果支持 Ifng 调控的模型，其中远端顺式调控元件以模块化的方式差异化招募关键转录因子，以启动由不同激活信号诱导的基因转录。
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