Rbm10 regulates inflammation development via alternative splicing of Dnmt3b, a DNA methyltransferase

• Project/Area Number: 26460574
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Hokkaido University
• Principal Investigator: Atsumi Toru 北海道大学, 遺伝子病制御研究所, 特任助教 (80360478)
• Co-Investigator(Kenkyū-buntansha): 上村 大輔 北海道大学, 遺伝子病制御研究所, 講師 (20391922)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 炎症 / DNAメチル化 / 選択的スプライシング / 選択性スプライシング / エピジェネティクス / スプライシング

Outline of Final Research Achievements

We previously discovered an inflammation induction mechanism in non-immune cells, the inflammation amplifier. Rbm10 deficiency suppressed NFκB-mediated chemokine and cytokine expression in vitro and inhibited an NFκB-dependent arthritis in vivo.
In Rbm10-deficient cells, NFκB reporter activity was suppressed, and p65 and p300 accumulation at the promoter sites of NFκB-responsive genes was decreased. Epigenetic alterations, including H3K9 acetylation, were also suppressed in contrast, DNA methylation is increased. Rbm10 increasing DNA methylation due to increase enzymatically active Dnmt3b2 and decrease enzymatically inactive Dnmt3b3. These two isoforms, thus increasing DNA methylation. Dnmt3b2 efficient associated with NFκB to methylate modulate the frequency of methylation in the promoter regions of NFκB targets such as inflammatory cytokines and chemokines. These results reveal a novel role of Rbm10 on inflammation development

Research Products

• [Journal Article] Breakpoint cluster region-mediated inflammation is dependent on casein kinase II. (2016)
  • Author(s): Meng, J., J-J Jiang, T. Atsumi, H. Bando, Y. Okuyama, L. Sabharwal, I. Nakagawa, H. Higuchi, M. Ota, M. Okawara, R. Ishitani, O. Nureki, D. Higo, Y. Arima, H. Ogura, D. Kamimura and M. Murakami.
  • Journal Title: J Immunol. Volume: 197(8) Issue: 8 Pages: 3111-3119
  • DOI: 10.4049/jimmunol.1601082
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Control of chronic inflammation by the inflammation amplifier and gateway reflexes. (2016)
  • Author(s): Ota, M., D. Kamimura, I. Nakagawa, H. Higuchi, Y. Tanaka, M. Fujita, S. Hiratsuka, M. Okawara, K. Murakami, T. Atsumi, Y. Arima and M. Murakami.
  • Journal Title: Advances in Medicine and Biology Volume: 104 Pages: 65-86
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells. (2016)
  • Author(s): Kamimura, D. Y. Arima, M. Tsuruoka, J-J Jiang, H. Bando, J. Meng, L. Sabharwal, A. Stofkova, N. Nishikawa, K. Higuchi, H. Ogura, T. Atsumi, M. Murakami.
  • Journal Title: Int Immunol. Volume: 28(3) Issue: 3 Pages: 117-126
  • DOI: 10.1093/intimm/dxv059
  • NAID: 120005851045
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immune Cell Gateways in the CNS Regulated by Regional Neural Stimulations. (2015)
  • Author(s): Kamimura, D., A. Stofkova, N. Nishikawa, T. Atsumi, Y. Arima, M. Murakami.
  • Journal Title: Clin Exp Neuroimmunol. Volume: 印刷中 Issue: 2 Pages: 120-128
  • DOI: 10.1111/cen3.12198
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Temporal expression of growth factors triggered by epiregulin regulates inflammation development. (2015)
  • Author(s): Harada, M., Kamimura, D., Arima, Y., Kohsaka, H., Nakatsuji, Y., Nishida, M., Atsumi, T., Meng, J., Bando, H., Singh, R., Sabharwal, L., Jiang, J. J., Kumai, N., Miyasaka, N., Sakoda, S., Yamauchi-Takihara, K., Ogura, H., Hirano, T. & Murakami, M.
  • Journal Title: J Immunol Volume: 194 Issue: 3 Pages: 1039-1046
  • DOI: 10.4049/jimmunol.1400562
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS. (2014)
  • Author(s): Sabharwal, L., Kamimura, D., Meng, J., Bando, H., Ogura, H., Nakayama, C., Jiang, J. J., Kumai, N., Suzuki, H., Atsumi, T., Arima, Y. & Murakami, M.
  • Journal Title: Journal of biochemistry Volume: 156 Issue: 6 Pages: 299-304
  • DOI: 10.1093/jb/mvu057
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inflammation Amplifier, a New Paradigm in Cancer Biology (2014)
  • Author(s): Atsumi T, Singh R, et al.
  • Journal Title: Cancer Research Volume: 74 Issue: 1 Pages: 8-14
  • DOI: 10.1158/0008-5472.can-13-2322
  • Peer Reviewed
• [Journal Article] The reverse-direction method links mass experimental data to human diseases. (2014)
  • Author(s): Ogura, H., Atsumi, T., Bando, H., Sabharwal, L., Yamada, M., Jiang, J. J., Nakamura, A., Arima, Y., Kamimura, D. & Murakami, M
  • Journal Title: Archivum immunologiae et therapiae experimentalis Volume: 62 Issue: 1 Pages: 41-45
  • DOI: 10.1007/s00005-013-0255-9
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Serum components mediate inflammation in the joints in a mouse model of reactive arthritis (2016)
  • Author(s): Toru Atsumi, Abhishek Kumar Singh, Daisuke Kamimura, Yasunobu Arima, Takuto Ohki, Yukihiro Sakashita, Naoki Nishikawa, Kotaro Higuchi, Ramnath Misra and Masaaki Murakami
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄県宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] 非免疫細胞における炎症増幅機構（炎症回路）制御遺伝子NPK1の機能解析 (2016)
  • Author(s): Toru Atsumi, Hideki Ogura, Jie Meng, Hidenori Bando, Lavannya Sabharwal, Jing-jing Jiang, Chiemi Nakayama, Yasunobu Arima, Daisuke Kamimura and Masaaki Murakami
  • Organizer: 第59回日本リウマチ学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-04-21
• [Presentation] Inflammation amplifier regulatory molecule NSZ1 controls NFkB specific chromatin accessibility via alternative splicing of a DNA methyltransferase (2015)
  • Author(s): Toru Atsumi, Jie Meng, Hidenori Bando, Lavannya Sabharwal, Jing-Jing Jiang, Yasunobu Arima, Daisuke Kamimura, Koichi Nakajima, Osamu Ohara and Masaaki Murakami
  • Organizer: 第44回日本免疫学会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] 炎症回路制御遺伝子ZnXはDNAメチル化酵素Dnmt3bの活性を調節することにより、標的遺伝子のプロモーター部位におけるクロマチン構造を制御する。 (2015)
  • Author(s): 熱海 徹、孟 潔、板東 英典、Sabharwal Lavannya、Jiang Jing-Jing、有馬 康伸、上村 大輔、小原 收、村上 正晃
  • Organizer: 第80回日本サイトカイン、インターフェロン学会
  • Place of Presentation: 東京工業大学（東京都目黒区）
  • Year and Date: 2015-07-17
• [Presentation] Genes responsible for inflammation also strongly correlate with human cancer development (2014)
  • Author(s): Toru Atsumi, Hideki Ogura, Jie Meng, Hidenori Bando, Lavannya Sabharwal, Jing-jing Jiang, Yasunobu Arima, Daisuke Kamimura and Masaaki Murakami
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 炎症アンプ制御遺伝子ZnXはNfkbと相互作用し、プロモーター.領域におけるクロマチン構造を制御する (2014)
  • Author(s): Toru Atsumi, Kokichi Katsunuma, Hironao Suzuki, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Hideki Ogura and Masaaki Murakami
  • Organizer: 第8回日本エピジェネティクス研究年会
  • Place of Presentation: 伊藤国際学術研究センター（東京都文京区）
  • Year and Date: 2014-05-25 – 2014-05-27
• [Remarks] 北海道大学遺伝子病制御研究所 分子神経免疫学
  • URL: http://www.igm.hokudai.ac.jp/neuroimmune/
• [Remarks] 北海道大学遺伝子病制御研究所
  • URL: http://www.igm.hokudai.ac.jp/
• [Remarks] 北海道大学遺伝子病制御研究所分子神経免疫学分野
  • URL: http://www.igm.hokudai.ac.jp/neuroimmune/index.html