A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes

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Science  16 Nov 2012:
Vol. 338, Issue 6109, pp. 975-980
DOI: 10.1126/science.1228309

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Helping T Helper Transcription

Members of the interferon response family of transcription factors (IRFs) are specifically expressed in immune cells and are known to regulate their differentiation. IRF4 and IRF8 regulate gene expression by binding to other transcription factors, which results in their recruitment to composite motifs in the genome. Although the specific mechanism of how this regulation works in some immune cells is understood, how it occurs in T cells is not clear because the transcription factors that normally partner with IRFs are absent. Using genomic analysis, Glasmacher et al. (p. 975, published online 13 September; see the Perspective by Martinez and Rao) now identify IRF4–AP-1 composite elements in T helper 17 (TH17) cells and show that IRF4 and the AP-1 factor Batf cooperatively assemble on a large array of genes required for TH17 cell differentiation and function. Assembly of such heterodimers was also observed in TH2 cells, B cells, and dendritic cells, which suggests the general importance of this motif in immune cell differentiation.


Interferon regulatory factor 4 (IRF4) and IRF8 regulate B, T, macrophage, and dendritic cell differentiation. They are recruited to cis-regulatory Ets-IRF composite elements by PU.1 or Spi-B. How these IRFs target genes in most T cells is enigmatic given the absence of specific Ets partners. Chromatin immunoprecipitation sequencing in T helper 17 (TH17) cells reveals that IRF4 targets sequences enriched for activating protein 1 (AP-1)–IRF composite elements (AICEs) that are co-bound by BATF, an AP-1 factor required for TH17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and TH17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 with BATF heterodimers and is also used in TH2, B, and dendritic cells. This genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals.

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