title: STAT5 Orchestrates Local Epigenetic Changes for Chromatin Accessibility and Rearrangements by Direct Binding to the TCRγ Locus.
abstract: The transcription factor STAT5, which is activated by IL-7R, controls chromatin accessibility and rearrangements of the TCRγ locus. Although STAT-binding motifs are conserved in Jγ promoters and Eγ enhancers, little is known about their precise roles in rearrangements of the TCRγ locus in vivo. To address this question, we established two lines of Jγ1 promoter mutant mice: one harboring a deletion in the Jγ1 promoter, including three STAT motifs (Jγ1P(Δ/Δ)), and the other carrying point mutations in the three STAT motifs in that promoter (Jγ1P(mS/mS)). Both Jγ1P(Δ/Δ) and Jγ1P(mS/mS) mice showed impaired recruitment of STAT5 and chromatin remodeling factor BRG1 at the Jγ1 gene segment. This resulted in severe and specific reduction in germline transcription, histone H3 acetylation, and histone H4 lysine 4 methylation of the Jγ1 gene segment in adult thymus. Rearrangement and DNA cleavage of the segment were severely diminished, and Jγ1 promoter mutant mice showed profoundly decreased numbers of γδ T cells of γ1 cluster origin. Finally, compared with controls, both mutant mice showed a severe reduction in rearrangements of the Jγ1 gene segment, perturbed development of γδ T cells of γ1 cluster origin in fetal thymus, and fewer Vγ3(+) dendritic epidermal T cells. Furthermore, interaction with the Jγ1 promoter and Eγ1, a TCRγ enhancer, was dependent on STAT motifs in the Jγ1 promoter. Overall, this study strongly suggests that direct binding of STAT5 to STAT motifs in the Jγ promoter is essential for local chromatin accessibility and Jγ/Eγ chromatin interaction, triggering rearrangements of the TCRγ locus.
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Keisuke
authors.initials: K
authors.lastname: Wagatsuma
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Shizue
authors.initials: S
authors.lastname: Tani-ichi
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Bingfei
authors.initials: B
authors.lastname: Liang
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shitara
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Ko
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan;
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Reproductive Engineering Team, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyachi
authors.affiliation: Reproductive Engineering Team, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Satsuki
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Yakult Central Institute, Kunitachi, Tokyo 186-8650, Japan;
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nanno
authors.affiliation: Yakult Central Institute, Kunitachi, Tokyo 186-8650, Japan;
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan;
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan; and Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; ikuta@virus.kyoto-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikuta
mesh_terms: D000107:Acetylation; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D053837:DNA Cleavage; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015321:Gene Rearrangement; D056426:Genetic Loci; D005854:Germ Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050799:STAT5 Transcription Factor