title: Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation.
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.
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Daisuke
authors: D
authors: Kurotaki
authors: Naoki
authors: N
authors: Osato
authors: Akira
authors: A
authors: Nishiyama
authors: Michio
authors: M
authors: Yamamoto
authors: Tatsuma
authors: T
authors: Ban
authors: Hideaki
authors: H
authors: Sato
authors: Jun
authors: J
authors: Nakabayashi
authors: Marina
authors: M
authors: Umehara
authors: Noriko
authors: N
authors: Miyake
authors: Naomichi
authors: N
authors: Matsumoto
authors: Masatoshi
authors: M
authors: Nakazawa
authors: Keiko
authors: K
authors: Ozato
authors: Tomohiko
authors: T
authors: Tamura
mesh_terms: D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D050835:Interferon Regulatory Factors / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
chemical_list: D015415:Biomarkers; D050835:Interferon Regulatory Factors; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000099185:Interferon Regulatory Factor-8; C000715468:Klf4 protein, mouse