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

Immunity. 2020 Oct 13;53(4):759-774.e9. doi: 10.1016/j.immuni.2020.07.018. Epub 2020 Aug 13.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dendritic Cells / metabolism*
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation / genetics
  • Interferon Regulatory Factors / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Chemokine / genetics
  • Transcription, Genetic / genetics

Substances

  • Interferon Regulatory Factors
  • Receptors, Chemokine
  • interferon regulatory factor-4
  • interferon regulatory factor-8