High Amount of Transcription Factor IRF8 Engages AP1-IRF Composite Elements in Enhancers to Direct Type 1 Conventional Dendritic Cell Identity

Sunkyung Kim, Prachi Bagadia, David A. Anderson, Tian Tian Liu, Xiao Huang, Derek J. Theisen, Kevin W. O'Connor, Ray A. Ohara, Arifumi Iwata, Theresa L. Murphy, Kenneth M. Murphy

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Development and function of conventional dendritic cell (cDC) subsets, cDC1 and cDC2, depend on transcription factors (TFs) IRF8 and IRF4, respectively. Since IRF8 and IRF4 can each interact with TF BATF3 at AP1-IRF composite elements (AICEs) and with TF PU.1 at Ets-IRF composite elements (EICEs), it is unclear how these factors exert divergent actions. Here, we determined the basis for distinct effects of IRF8 and IRF4 in cDC development. Genes expressed commonly by cDC1 and cDC2 used EICE-dependent enhancers that were redundantly activated by low amounts of either IRF4 or IRF8. By contrast, cDC1-specific genes relied on AICE-dependent enhancers, which required high IRF concentrations, but were activated by either IRF4 or IRF8. IRF8 was specifically required only by a minority of cDC1-specific genes, such as Xcr1, which could distinguish between IRF8 and IRF4 DNA-binding domains. Thus, these results explain how BATF3-dependent Irf8 autoactivation underlies emergence of the cDC1-specific transcriptional program.

Original languageEnglish
Pages (from-to)759-774.e9
JournalImmunity
Volume53
Issue number4
DOIs
StatePublished - Oct 13 2020

Keywords

  • AICE
  • AP-1-IRF composite element
  • EICE
  • Ets-IRF composite element
  • IRF
  • IRF4
  • IRF8
  • cis-regulatory element
  • dendritic cell identity
  • interferon regulatory factor
  • transcriptional program

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