Investigation of the physiological functions of histone modifying enzymes by gene targeting techniques

• Project/Area Number: 25430170
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Genome biology
• Research Institution: Shokei Junior College (2015); University of Miyazaki (2013-2014)
• Principal Investigator: Kikuchi Hidehiko 尚絅大学短期大学部, その他部局等, 教授 (10301384)
• Co-Investigator(Renkei-kenkyūsha): NISHITOH Hideki 宮崎大学, 医学部, 教授 (00332627)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: エピジェネティクス / B細胞分化 / 遺伝子ノックアウト / ヒストンアセチル化 / DT40 / B細胞 / 転写制御 / ヒストン / ヒストンアセチル化酵素 / 遺伝子ターゲッティング / GCN5 / PCAF / 免疫グロブリン / histone acetylation / gene expression / B cell differentiation / epigenetics / Blimp-1 / IRF-4

Outline of Final Research Achievements

To investigate the physiological roles of histone modifying enzymes, in this study, I examined the effects of deficiency of their genes on various cellular functions using gene targeting techniques in the chicken immature B cell line DT40.
(1) Histone acetyltransferases GCN5 and PCAF participate in B cell differentiation through controlling gene expression of some B cell-specific transfactors in an opposite manner (GCN5: promoting effect, PCAF: inhibitory effect). (2) GCN5 is involved in regulation of prolonged ER stress-induced apoptosis through controlling Bcl-2 gene expression. (3) GCN5 and PCAF take part in transcriptional regulation of the IgM H-chain gene and play key roles in epigenetic regulation of B cell functions.

Research Products

• [Journal Article] The histone acetyltransferase p300/CBP-associated factor acts as an effective suppressor of secretory immunoglobulin synthesis in immature B cells (2015)
  • Author(s): Hidehiko Kikuchi, Masami Nakayama, Chikage Kawai, Futoshi Kuribayashi, Hitomi Mimuro, Shinobu Imajoh-Ohmi, Nishitoh H, Yasunari Takami, and Tatsuo Nakayama
  • Journal Title: Microbiol. Immunol Volume: 59 Issue: 4 Pages: 243-247
  • DOI: 10.1111/1348-0421.12237
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lack of GCN5 remarkably enhances the resistance against prolonged endoplasmic reticulum stress-induced apoptosis through up-regulation of Bcl-2 gene expression. (2015)
  • Author(s): Kikuchi H, Kuribayashi F, Mimuro H, Imajoh-Ohmi S, Nakayama M, Takami Y, Nishitoh H, Nakayama T:
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 463 Issue: 4 Pages: 870-875
  • DOI: 10.1016/j.bbrc.2015.06.027
  • Peer Reviewed
• [Journal Article] Paired box gene 5 isoforms A and B have different functions in transcriptional regulation of B cell development-related genes in immature B cells. (2015)
  • Author(s): Kikuchi H, Nakayama M, Kuribayashi F, Mimuro H, Imajoh-Ohmi S, Nishitoh H, Takami Y, Nakayama T:
  • Journal Title: Microbiol. Immunol. Volume: 59 Issue: 7 Pages: 426-431
  • DOI: 10.1111/1348-0421.12272
  • Peer Reviewed
• [Journal Article] Histone acetyltransferase PCAF is involved in transactivation of Bcl-6 and Pax5 genes in immature B cells. (2015)
  • Author(s): Kikuchi H, Nakayama M, Kuribayashi F, Mimuro H, Imajoh-Ohmi S, Nishitoh H, Nakayama T.
  • Journal Title: Biochem Biophys Res Commun. Nov 20;(3):509-13. Volume: 467 Issue: 3 Pages: 509-513
  • DOI: 10.1016/j.bbrc.2015.10.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protein kinase Cθ gene expression is oppositely regulated by GCN5 and EBF1 in immature B cells. (2014)
  • Author(s): Kikuchi H, Nakayama M, Kuribayashi F, Imajoh-Ohmi S, Nishitoh H, Takami Y, Nakayama T
  • Journal Title: FEBS Lett Volume: 588 Issue: 9 Pages: 1739-1742
  • DOI: 10.1016/j.febslet.2014.03.025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] GCN5 is involved in regulation of immunoglobulin heavy chain gene expression in immature B cells. (2014)
  • Author(s): Kikuchi H., Nakayama M., Kuribayashi F., Imajoh-Ohmi S., Nishitoh H., Takami Y., Nakayama T.
  • Journal Title: Gene Volume: 544 Issue: 1 Pages: 19-24
  • DOI: 10.1016/j.gene.2014.04.030
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] GCN5 is essential for IRF-4 gene expression followed by transcriptional activation of Blimp-1 in immature B cells. (2014)
  • Author(s): Kikuchi H, Nakayama M, Kuribayashi F, Imajoh-Ohmi S, Nishitoh H, Takami Y, Nakayama T.
  • Journal Title: J Leukoc Biol Volume: 95 Issue: 3 Pages: 399-404
  • DOI: 10.1189/jlb.0413232
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Down-regulation of Fas-mediated apoptosis by plasma transglutaminase factor XIII that catalyzes fetal-specific cross-link of the Fas molecule. (2014)
  • Author(s): Kikuchi H, Kuribayashi F, Imajoh-Ohmi S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Issue: 1 Pages: 13-17
  • DOI: 10.1016/j.bbrc.2013.10.163
  • Peer Reviewed
• [Presentation] プロテインキナーゼCθの遺伝子発現はGCN5とEBF1によって正負に制御されている (2015)
  • Author(s): 菊池秀彦、中山雅美、栗林太、三室仁美、大海忍、西頭英起、高見恭成、中山建男
  • Organizer: 日本エピジェネティクス研究会
  • Place of Presentation: 東京一ツ橋学術総合センター
  • Year and Date: 2015-05-25
• [Presentation] Down-regulation of Fas-mediated apoptosis by plasma transglutaminase factor XIII that catalyzes fetal-specific cross-link of the Fas molecule (2014)
  • Author(s): Hidehiko Kikuchi, Futoshi Kuribayashi, Hitomi Mimuro, Hideki Nishitoh, Shinobu Imajoh-Ohmi
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] GCN5 is essential for IRF-4 gene expression followed by transcriptional activation of Blimp-1 in immature B cells (2014)
  • Author(s): Hidehiko Kikuchi, Masami Nakayama, Futoshi Kuribayashi, Shinobu Imajoh-Ohmi, Hideki Nishitoh, Yasunari Takami, Tatsuo Nakayama
  • Organizer: 第８回日本エピジェネティックス研究会年会
  • Place of Presentation: 伊藤国際学術研究センター（東京大学構内）
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] GCN5はDNAポリメラーゼηの発現制御を介して細胞を紫外線から保護する (2013)
  • Author(s): 菊池秀彦、栗林太、大海忍、西頭英起、高見恭成、中山建男
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良県新公会堂
• [Presentation] GCN5 is involved in regulation of immunoglobulin heavy chain gene expression in immature B cells (2013)
  • Author(s): 菊池秀彦、中山雅美、栗林太、大海忍、西頭英起、高見恭成、中山建男
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Remarks] KIKUCHI LAB.
  • URL: http://kikuchi-biolchem.jimdo.com
• [Remarks] 宮崎大学医学部機能生化学分野ホームページ
  • URL: http://www.med.miyazaki-u.ac.jp/2bio/index.html
• [Remarks] 宮崎大学医学部機能制御学講座機能生化学分野
  • URL: http://www.med.miyazaki-u.ac.jp/2bio/index.html