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

Yuta Mishima, Changshan Wang, Satoru Miyagi, Atsunori Saraya, Hiroyuki Hosokawa, Makiko Mochizuki-Kashio, Yaeko Nakajima-Takagi, Shuhei Koide, Masamitsu Negishi, Goro Sashida, Taku Naito, Tomoyuki Ishikura, Atsushi Onodera, Toshinori Nakayama, Daniel G. Tenen, Naoto Yamaguchi, Haruhiko Koseki, Ichiro Taniuchi and Atsushi Iwama ()
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Yuta Mishima: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Changshan Wang: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Satoru Miyagi: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Atsunori Saraya: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, 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
Yaeko Nakajima-Takagi: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Shuhei Koide: Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, 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
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

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6872

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