title: A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes.
abstract: 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 (T(H)17) 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 T(H)17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and T(H)17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 with BATF heterodimers and is also used in T(H)2, B, and dendritic cells. This genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals.
authors.affiliation: Department of Discovery Immunology, Genentech, Incorporated, South San Francisco, CA 94080, USA.
authors.forename: Elke
authors.initials: E
authors.lastname: Glasmacher
authors.forename: Smita
authors.initials: S
authors.lastname: Agrawal
authors.forename: Abraham B
authors.initials: AB
authors.lastname: Chang
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zeng
authors.forename: Bryan
authors.initials: B
authors.lastname: Vander Lugt
authors.forename: Aly A
authors.initials: AA
authors.lastname: Khan
authors.forename: Maria
authors.initials: M
authors.lastname: Ciofani
authors.forename: Chauncey J
authors.initials: CJ
authors.lastname: Spooner
authors.forename: Sascha
authors.initials: S
authors.lastname: Rutz
authors.forename: Jason
authors.initials: J
authors.lastname: Hackney
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Escalante
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D006801:Humans; D056747:Immunomodulation / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050436:Regulatory Elements, Transcriptional; D058504:Th17 Cells / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050835:Interferon Regulatory Factors; D018808:Transcription Factor AP-1; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse