A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes

• Published in: Nature immunology Vol. 22; no. 3; pp. 301 - 311
• Main Authors: Murakami, Koichi, Sasaki, Haruka, Nishiyama, Akira, Kurotaki, Daisuke, Kawase, Wataru, Ban, Tatsuma, Nakabayashi, Jun, Kanzaki, Satoko, Sekita, Yoichi, Nakajima, Hideaki, Ozato, Keiko, Kimura, Tohru, Tamura, Tomohiko
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2021; Nature Publishing Group
• Subjects: 631/250/2502; 631/250/2504/133/2505; 631/250/2504/342; Animals; Antigens, Ly - genetics; Antigens, Ly - metabolism; Biomedical and Life Sciences; Biomedicine; Bone Marrow Cells; Cell differentiation; Cell Lineage; Cells, Cultured; Core Binding Factor alpha Subunits - genetics; Core Binding Factor alpha Subunits - metabolism; Core Binding Factor beta Subunit - genetics; Core Binding Factor beta Subunit - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Enhancer Elements, Genetic; Enhancers; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Developmental; Hematopoietic stem cells; Immunology; Infectious Diseases; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Leukocytes (neutrophilic); Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monocytes; Monocytes - immunology; Monocytes - metabolism; Myeloid Progenitor Cells - immunology; Myeloid Progenitor Cells - metabolism; Phenotype; Progenitor cells; Signal Transduction; Transcription factors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-00871-y

The transcription factor IRF8 is essential for the development of monocytes and dendritic cells (DCs), whereas it inhibits neutrophilic differentiation. It is unclear how Irf8 expression is regulated and how this single transcription factor supports the generation of both monocytes and DCs. Here, we identified a RUNX–CBFβ-driven enhancer 56 kb downstream of the Irf8 transcription start site. Deletion of this enhancer in vivo significantly decreased Irf8 expression throughout the myeloid lineage from the progenitor stages, thus resulting in loss of common DC progenitors and overproduction of Ly6C + monocytes. We demonstrated that high, low or null expression of IRF8 in hematopoietic progenitor cells promotes differentiation toward type 1 conventional DCs, Ly6C + monocytes or neutrophils, respectively, via epigenetic regulation of distinct sets of enhancers in cooperation with other transcription factors. Our results illustrate the mechanism through which IRF8 controls the lineage choice in a dose-dependent manner within the myeloid cell system. The transcription factor IRF8 is required for both DC and monocyte differentiation from common myeloid progenitors. Tamura and colleagues identify an enhancer (+56 kb) in the Irf8 locus that regulates early myeloid lineage choice.