title: A Histone Methyltransferase ESET Is Critical for T Cell Development.
abstract: ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET(-/-) thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET(-/-) thymocytes. Indeed, genetic depletion of FcγRIIB in ESET(-/-) thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET(-/-) mice. Therefore, impaired T cell development in ESET(-/-) mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.
authors: Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Shoichi
authors: S
authors: Takikita
authors: Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Ryunosuke
authors: R
authors: Muro
authors: Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan;
authors: Toshiyuki
authors: 0000-0002-4549-7116
authors: T
authors: Takai
authors: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Takeshi
authors: T
authors: Otsubo
authors: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Yuki I
authors: YI
authors: Kawamura
authors: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Taeko
authors: 0000-0002-3411-1097
authors: T
authors: Dohi
authors: Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Hiroyo
authors: H
authors: Oda
authors: Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors: Masayuki
authors: 0000-0002-4748-4730
authors: M
authors: Kitajima
authors: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba 272-8561, Japan;
authors: Kenshiro
authors: K
authors: Oshima
authors: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba 272-8561, Japan; Cooperative Major in Advanced Health Science, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan;
authors: Masahira
authors: M
authors: Hattori
authors: Integrated Database Unit, Advanced Center for Computing and Communication, RIKEN, Wako, Saitama 351-0198, Japan;
authors: Takaho A
authors: 0000-0002-2801-2463
authors: TA
authors: Endo
authors: Integrated Database Unit, Advanced Center for Computing and Communication, RIKEN, Wako, Saitama 351-0198, Japan;
authors: Tetsuro
authors: T
authors: Toyoda
authors: Division of Cell Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132; and.
authors: John
authors: J
authors: Weis
authors: Cellular Memory Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors: Yoichi
authors: Y
authors: Shinkai
authors: Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan; hsuzuki@ri.ncgm.go.jp.
authors: Harumi
authors: H
authors: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000502:physiology
chemical_list: C080571:Fc gamma receptor IIB; D006657:Histones; D017452:Receptors, IgG; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D008239:Lysine