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Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development

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  • Yuta Mishima

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan
    Cancer Science Institute, National University of Singapore, and Harvard Stem Cell Institute, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA)

  • Changshan Wang

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Satoru Miyagi

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Atsunori Saraya

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Hiroyuki Hosokawa

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan)

  • Makiko Mochizuki-Kashio

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Yaeko Nakajima-Takagi

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Shuhei Koide

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Masamitsu Negishi

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan)

  • Goro Sashida

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

  • Taku Naito

    (Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan)

  • Tomoyuki Ishikura

    (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)

  • Atsushi Onodera

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan)

  • Toshinori Nakayama

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan)

  • Daniel G. Tenen

    (Cancer Science Institute, National University of Singapore, and Harvard Stem Cell Institute, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA)

  • Naoto Yamaguchi

    (Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan)

  • Haruhiko Koseki

    (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)

  • Ichiro Taniuchi

    (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)

  • Atsushi Iwama

    (Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
    JST, CREST, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan)

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.

Suggested Citation

  • Yuta Mishima & Changshan Wang & Satoru Miyagi & Atsunori Saraya & Hiroyuki Hosokawa & Makiko Mochizuki-Kashio & Yaeko Nakajima-Takagi & Shuhei Koide & Masamitsu Negishi & Goro Sashida & Taku Naito & T, 2014. "Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6872
    DOI: 10.1038/ncomms6872
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