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

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Science  13 Sep 2012:
DOI: 10.1126/science.1228309

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IRF4 and IRF8 regulate B, T, macrophage, and dendritic cell differentiation. They are recruited to cis-regulatory Ets-IRF composite elements (EICE) by PU.1 or Spi-B. How these IRFs target genes in most T cells is enigmatic given absence of specific Ets partners. ChIPseq in Th17 cells reveals that IRF4 targets sequences enriched for AP-1-IRF composite elements (AICE) 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 and promote gene activation and Th17 differentiation. The AICE motif directs assembly of IRF4 or 8 with BATF heterodimers and is also utilized 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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