Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation
In: Blood, Jg. 121 (2013-03-07), S. 1839-1849
Online
unknown
Zugriff:
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.
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Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation
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Autor/in / Beteiligte Person: | Ozato, Keiko ; Nishiyama, Akira ; Nakazawa, Masatoshi ; Osato, Naoki ; Sato, Hideaki ; Kurotaki, Daisuke ; Ban, Tatsuma ; Tamura, Tomohiko ; Umehara, Marina ; Nakabayashi, Jun ; Yamamoto, Michio ; Matsumoto, Naomichi ; Miyake, Noriko |
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Zeitschrift: | Blood, Jg. 121 (2013-03-07), S. 1839-1849 |
Veröffentlichung: | American Society of Hematology, 2013 |
Medientyp: | unknown |
ISSN: | 1528-0020 (print) ; 0006-4971 (print) |
DOI: | 10.1182/blood-2012-06-437863 |
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