The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells.
Intestinal regulatory T cells (Treg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal Treg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in Treg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of Treg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.
1] Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [2] Laboratory for Immune Regulation, Graduate School of Medicine, Chiba University, Chiba, Japan. [3] Laboratory for Bioenvironmental Epigenetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [4] Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan. [5].
Yuuki
Y
Obata
1] Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [2] Laboratory for Bioenvironmental Epigenetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [3] [4].
Yukihiro
Y
Furusawa
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Takaho A
TA
Endo
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Jafar
J
Sharif
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Daisuke
D
Takahashi
1] Laboratory for Gut Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [2] PRESTO, Japan Science and Technology Agency, Saitama, Japan.
Koji
K
Atarashi
Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Chiba, Japan.
Manabu
M
Nakayama
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Satoshi
S
Onawa
1] Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [2] Laboratory for Bioenvironmental Epigenetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Yumiko
Y
Fujimura
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Masumi
M
Takahashi
1] PRESTO, Japan Science and Technology Agency, Saitama, Japan. [2] Laboratory for Immune Regeneration, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Tomokatsu
T
Ikawa
Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
Takeshi
T
Otsubo
Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
Yuki I
YI
Kawamura
Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
Taeko
T
Dohi
Laboratory of Epigenetics, Institute for Protein Research, Osaka University, Osaka, Japan.
Shoji
S
Tajima
Laboratory of Cell Engineering, Department of Frontier Research, Kazusa DNA Research Institute, Chiba, Japan.
Hiroshi
H
Masumoto
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Osamu
O
Ohara
1] Laboratory for Gut Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [2] CREST, Japan Science and Technology Agency, Saitama, Japan.
Kenya
K
Honda
Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Shohei
S
Hori
1] Laboratory for Immune Regulation, Graduate School of Medicine, Chiba University, Chiba, Japan. [2] Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan. [3] Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Hiroshi
H
Ohno
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Haruhiko
H
Koseki
1] Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [2] Laboratory for Bioenvironmental Epigenetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. [3] Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan. [4] PRESTO, Japan Science and Technology Agency, Saitama, Japan. [5].
Koji
K
Hase
D019264:Adoptive Transfer; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D003013:Clostridium / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D003106:Colon / Q000276:immunology* / Q000382:microbiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D007376:Interleukin-2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064307:Microbiota / Q000276:immunology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D013559:Symbiosis / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007376:Interleukin-2; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse