title: Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development.
abstract: During T-cell development, Cd8 expression is controlled via dynamic regulation of its cis-regulatory enhancer elements. Insufficiency of enhancer activity causes variegated Cd8 expression in CD4(+)CD8(+) double-positive (DP) thymocytes. Brd1 is a subunit of the Hbo1 histone acetyltransferase (HAT) complex responsible for acetylation of histone H3 at lysine 14 (H3K14). Here we show that deletion of Brd1 in haematopoietic progenitors causes variegated expression of Cd8, resulting in the appearance of CD4(+)CD8(-)TCRβ(-/low) thymocytes indistinguishable from DP thymocytes in their properties. Biochemical analysis confirms that Brd1 forms a HAT complex with Hbo1 in thymocytes. ChIP analysis demonstrates that Brd1 localizes at the known enhancers in the Cd8 genes and is responsible for acetylation at H3K14. These findings indicate that the Brd1-mediated HAT activity is crucial for efficient activation of Cd8 expression via acetylation at H3K14, which serves as an epigenetic mark that promotes the recruitment of transcription machinery to the Cd8 enhancers.
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [3] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan [4] Cancer Science Institute, National University of Singapore, and Harvard Stem Cell Institute, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hosokawa
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Negishi
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Molecular Immunology, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, IMS-RCAI, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ishikura
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Onodera
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Cancer Science Institute, National University of Singapore, and Harvard Stem Cell Institute, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, IMS-RCAI, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Research Center for Integrative Medical Sciences, IMS-RCAI, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan [2] JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000107:Acetylation; D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D051548:Histone Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D000092468:Bromodomain Containing Proteins
chemical_list: D016827:CD8 Antigens; D051548:Histone Acetyltransferases; D006657:Histones; C562256:BRD1 protein, mouse; D000092468:Bromodomain Containing Proteins; C525638:Kat7 protein, mouse