Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation

Daisuke Kurotaki, Naoki Osato, Akira Nishiyama, Michio Yamamoto, Tatsuma Ban, Hideaki Sato, Jun Nakabayashi, Marina Umehara, Noriko Miyake, Naomichi Matsumoto, Masatoshi Nakazawa, Keiko Ozato, Tomohiko Tamura

Research output: Contribution to journalArticlepeer-review

144 Citations (Scopus)

Abstract

Monocytes regulate host defenses, inflammation, and tissue homeostasis. The transcription factor interferon regulatory factor-8 (IRF8) stimulates monocyte/macrophage differentiation, yet genome-wide understanding of the differentiation program initiated by IRF8 is lacking. By combining chromatin immunoprecipitation sequencing with gene expression profiling, we show that during IRF8-dependent monocyte differentiation, IRF8 binding occurs at both promoter-proximal and promotor-distal regions together with the transcription factor PU.1 and is associated with gene induction. Many of the promoter-distal IRF8 binding sites show an increase in histone H3 lysine 4 monomethylation, a signature for enhancers. However, about half the IRF8-induced genes were not bound by IRF8, suggesting the involvement of downstream transcription factors. Analysis of DNA motifs in cis-regulatory elements of these indirect IRF8 target genes predicted that Kr üppel-like factor-4 (KLF4)-essential for Ly6C + monocyte development-is one such factor. Indeed, monocyte development in Irf8-/- mice is as defective as that in Klf4 -/- chimeric mice. Moreover, Irf8-/- monocytedendritic cell progenitors do not express Klf4 messenger RNA. Introduction of KLF4 into an Irf8-/- myeloid progenitor cell line induced a subset of IRF8 target genes and caused partial monocyte differentiation. Taken together, our present results uncover genome-wide behavior of IRF8 and identify an IRF8-KLF4 axis that operates during monocyte differentiation.

Original languageEnglish
Pages (from-to)1839-1849
Number of pages11
JournalBlood
Volume121
Issue number10
DOIs
Publication statusPublished - 2013 Mar 7
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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