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23319570
Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation.

Blood, 2013/3/07;121(10):1839-49.

Kurotaki D[1], Osato N, Nishiyama A, Yamamoto M, Ban T, Sato H, Nakabayashi J, Umehara M, Miyake N, Matsumoto N, Nakazawa M, Ozato K, Tamura T

Affiliations

PMID: 23319570DOI: 10.1182/blood-2012-06-437863

Impact factor: 25.476

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 Krüppel-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(-/-) monocyte-dendritic 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.
MeSH terms
Animals; Binding Sites; Biomarkers; Cell Differentiation; Cells, Cultured; Chromatin Immunoprecipitation; Gene Expression Profiling; Gene Expression Regulation; Genome; Interferon Regulatory Factors; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Transcription, Genetic
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