Physical and functional interaction among Irf8 enhancers during dendritic cell differentiation
Takaya Yamasaki,
Akira Nishiyama,
Nagomi Kurogi,
Koutarou Nishimura,
Shion Nishida,
Daisuke Kurotaki,
Tatsuma Ban,
Jordan A. Ramilowski,
Keiko Ozato,
Atsushi Toyoda,
Tomohiko Tamura
Affiliations
Takaya Yamasaki
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Akira Nishiyama
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Nagomi Kurogi
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Koutarou Nishimura
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Shion Nishida
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Laboratory of Stem Cell Biology, Department of Biosciences, Kitasato University School of Science, Sagamihara, Kanagawa, Japan
Daisuke Kurotaki
Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
Tatsuma Ban
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Jordan A. Ramilowski
Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, Japan
Keiko Ozato
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Atsushi Toyoda
Comparative Genomics Laboratory, National Institute of Genetics, Mishima, Shizuoka, Japan; Advanced Genomics Center, National Institute of Genetics, Mishima, Shizuoka, Japan
Tomohiko Tamura
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, Japan; Corresponding author
Summary: The production of type 1 conventional dendritic cells (cDC1s) requires high expression of the transcription factor IRF8. Three enhancers at the Irf8 3′ region function in a differentiation stage-specific manner. However, whether and how these enhancers interact physically and functionally remains unclear. Here, we show that the Irf8 3′ enhancers directly interact with each other and contact the Irf8 gene body during cDC1 differentiation. The +56 kb enhancer, which functions from multipotent progenitor stages, activates the other 3′ enhancers through an IRF8-dependent transcription factor program, that is, in trans. Then, the +32 kb enhancer, which operates in cDC1-committed cells, reversely acts in cis on the other 3′ enhancers to maintain the high expression of Irf8. Indeed, mice with compound heterozygous deletion of the +56 and +32 kb enhancers are unable to generate cDC1s. These results illustrate how multiple enhancers cooperate to induce a lineage-determining transcription factor gene during cell differentiation.
