Aberrant gene transcription based on chromatin structure in rheumatoid arthritis synovial fibroblasts

• Project/Area Number: 16K09903
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Saitama Medical University
• Principal Investigator: Araki Yasuto 埼玉医科大学, 医学部, 講師 (10580839)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 関節リウマチ / エピジェネティクス / クロマチン / ヒストンメチル化 / 転写因子 / リウマチ学

Outline of Final Research Achievements

Rheumatoid arthritis (RA) is a disease in which the etiology is unknown and the treatment is difficult. To elucidate epigenetic dysregulation in RA, we examined the mechanisms of aberrant gene transcription based on the interaction of chromatin structure and transcription factors (TFs) in RA synovial fibroblasts (SFs). We analyzed chromatin structure by investigating histone modifications with ChIP-seq in RASFs. We examined open chromatin regions that regulate gene transcription by FAIRE-seq. We identified SOX11 as a RASF-specific TF by analyzing TF consensus motifs of the regions.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ（RA）特異的な転写因子としてSOX11を同定したが、SOX11はRA線維芽細胞（SF）の活性化に必要な事が示唆される。つまり、SOX11を標的とした治療を行う事によりSOX11の機能を低下させる事ができれば、RASFsの活性化を抑制する事が期待される。このように、今回の結果は新規のRA治療につながる重要なものである。

Research Products

• [Journal Article] Aberrant gene expression of histone lysine methyltransferases and demethylases in rheumatoid arthritis synovial fibroblasts (2018)
  • Author(s): Araki Y, Aizaki Y, Sato K, Oda H, Kurokawa R, Mimura T
  • Journal Title: Clin Exp Rheumatol Volume: 36 Pages: 314-316
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase gene activation resulting from disordered epigenetic mechanisms in rheumatoid arthritis (2017)
  • Author(s): Araki Y, Mimura T
  • Journal Title: Int J Mol Sci Volume: 18 Issue: 5 Pages: 905-905
  • DOI: 10.3390/ijms18050905
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The histone modification code in the pathogenesis of autoimmune diseases (2017)
  • Author(s): Araki Y, Mimura T
  • Journal Title: Mediators of Inflammation Volume: 2017 Pages: 2608605-2608605
  • DOI: 10.1155/2017/2608605
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 関節リウマチ滑膜におけるヒストンメチル化とIL-6誘導によるMMP遺伝子 (2017)
  • Author(s): 荒木靖人
  • Journal Title: Keynote R・A Volume: 5 Pages: 14-18
• [Journal Article] The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape (2016)
  • Author(s): Araki Y, Mimura T
  • Journal Title: Journal of Immunology Research Volume: 2016 Pages: 6290682-6290682
  • DOI: 10.1155/2016/6290682
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histone Methylation and STAT-3 Differentially Regulate Interleukin-6-Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts. (2016)
  • Author(s): Araki Y, Tsuzuki Wada T, Aizaki Y, Sato K, Yokota K, Fujimoto K, Kim YT, Oda H, Kurokawa R, Mimura
  • Journal Title: Arthritis Rheumatol. Volume: 68 Issue: 5 Pages: 1111-23
  • DOI: 10.1002/art.39563
  • Peer Reviewed / Open Access
• [Presentation] 関節リウマチ滑膜線維芽細胞におけるヒストンH3リシン4メチル基転移酵素によるケモカイン遺伝子転写制御の異常 (2017)
  • Author(s): 荒木靖人、相崎良美、横田和浩、梶山浩、舟久保ゆう、佐藤浩二郎、織田弘美、三村俊英
  • Organizer: 第61回日本リウマチ学会総会・学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2017-04-20
• [Presentation] Histone lysine methylation and STAT3 differentially regulate constitutive and IL-6-induced MMP gene activation in rheumatoid arthritis synovial fibroblasts (2017)
  • Author(s): Araki Y, Mimura T
  • Organizer: Keystone symposia, Epigenetics and human disease: progress from mechanisms to therapeutics
  • Place of Presentation: Sheraton Seattle Hotel, Seattle, USA
  • Year and Date: 2017-01-29
  • Int'l Joint Research
• [Presentation] 関節リウマチ滑膜線維芽細胞におけるH3K4ヒストンメチル基転移酵素によるケモカイン遺伝子活性化の機構 (2017)
  • Author(s): 荒木靖人、和田琢、相崎良美、油谷浩幸、三村俊英
  • Organizer: 第11回日本エピジェネティクス研究会年会
• [Presentation] Histone lysine methylation and STAT3 differentially regulate constitutive and IL-6-induced MMPs gene activation in rheumatoid arthritis synovial fibroblasts (2016)
  • Author(s): Y. Araki, TT. Wada, Y. Aizaki, K. Sato T. Mimura
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター・ラグナガーデンホテル（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] Histone lysine methylation and STAT3 differentially regulate constitutive and IL-6-induced MMPs gene activation in rheumatoid arthritis synovial fibroblasts (2016)
  • Author(s): Araki Y, Wada TT, Aizaki Y, Yokota K, Kajiyama H, Asanuma YF, Sato K, Oda H, Mimura T
  • Organizer: American College of Rheumatology, the Annual Scientific Meeting 2016
  • Place of Presentation: Washington DC Convention Center, Washington DC, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Histone methylation in γδ T cells as a biomarker of Behcet’s disease activity (2016)
  • Author(s): Aizaki Y, Araki Y, Sato K, Yokota K, Mimura T
  • Organizer: American College of Rheumatology, the Annual Scientific Meeting 2016
  • Place of Presentation: Washington DC Convention Center, Washington DC, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] 関節リウマチ滑膜線維芽細胞におけるヒストンメチル化とSTAT3によるIL-6誘導性MMP遺伝子活性化 (2016)
  • Author(s): 荒木靖人、和田琢、相崎良美、佐藤浩二郎、織田弘美、三村俊英
  • Organizer: 第2回日本骨免疫学会
  • Place of Presentation: ホテルモントレ沖縄スパ＆リゾート（沖縄県国頭郡）
  • Year and Date: 2016-07-06
• [Presentation] Altered profiles of histone lysine methylation affect MMP gene transcription in rheumatoid arthritis synovial fibroblasts (2016)
  • Author(s): Araki Y, Wada TT, Aizaki Y, Kajiyama H, Yokota K, Sato K, Asanuma YF, Kim YT, Oda H, Mimura T
  • Organizer: Annual European Congress of Rheumatology EULAR 2016
  • Place of Presentation: ExCel London, London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] The epigenetic mechanism of constitutive and IL-6-induced MMP gene activation in rheumatoid arthritis synovial fibroblasts (2016)
  • Author(s): Yasuto Araki, Takuma Tsuzuki Wada, Yoshimi Aizaki, Hiroshi Kajiyama, Kazuhiro Yokota, Kojiro Sato, Yu Funakubo Asanuma, Yoon-Taek Kim, Hiromi Oda, Toshihide Mimura
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21
• [Book] Epigenetics in Human Disease, 2nd edition (2018)
  • Author(s): Araki Y, Mimura T
  • Total Pages: 34
  • Publisher: Elsevier
• [Remarks] 埼玉医科大学リウマチ膠原病科ホームページ
  • URL: http://www.saitama-med.ac.jp/uinfo/riumachi/Dr.Araki.html