The emerging roles of long noncoding RNA in inflammatory diseases.

• Project/Area Number: 18K08895
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Fukushima Medical University
• Principal Investigator: SEKIMATA Masayuki 福島県立医科大学, 医学部, 准教授 (80250190)
• Co-Investigator(Kenkyū-buntansha): 関亦 明子 山形大学, 医学部, 准教授 (50321823) ; 伊関 憲 福島県立医科大学, 医学部, 教授 (70332921)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 長鎖非コードRNA / サイトカイン / 炎症 / エピジェネティクス / 転写制御 / 免疫細胞 / 全身性炎症反応症候群 / 炎症制御 / 遺伝子発現調節 / インターロイキン９ / サイレンサー / クロマチン / 非コードRNA / ゲノム編集マウス / シス調節領域 / ヘルパーT細胞 / lncRNA / 遺伝子発現

Outline of Final Research Achievements

Systemic inflammatory response syndrome such as sepsis is a fatal disease caused by enhanced proinflammatory cytokine production, and effective therapeutics are not currently available. Here, we focused on the proinflammatory cytokine interleukin-9 (IL-9) that is thought to be implicated in the pathogenesis of human severe bronchial asthma. We identified a novel long noncoding RNA (lncRNA) that is transcribed from the IL-9 silencer element we previously discovered. Moreover, we revealed that the lncRNA is associated with several specific nuclear proteins and the formation of lncRNA-protein complex is the molecular mechanism responsible for transcriptional repression through directly acting on the specific genomic DNA regions. Finally, we aimed to develop an effective and novel therapeutic strategy for inflammatory disorders through the employment of the modified function of lncRNA-protein complex.

Academic Significance and Societal Importance of the Research Achievements

敗血症などの全身性炎症反応症候群は、病原体感染を契機とした過剰なサイトカイン産生を主因とする致死性疾患であるが、有効な治療法は確立していない。研究代表者は、サイトカイン遺伝子近傍のサイレンサー領域から転写されるlncRNAが、タンパク質複合体として染色体DNAの構造変換を制御することでサイトカイン産生を調節するレギュレーター機能を有していることを解明した。本研究成果は、タンパク質情報をコードしていないlncRNAの機能解明が世界的にも進んでいないことから学術的意義があるばかりか、lncRNAによるサイトカイン産生調節能力を活用した新規治療法の開発に繋がることから社会的にも意義があると考える。

Research Products

• [Journal Article] Deletion of PIN4 Suppresses the Protein Transport Defects Caused by sec12-4 Mutation in Saccharomyces cerevisiae (2020)
  • Author(s): Murakami-Sekimata Akiko、Sekimata Masayuki、Sato Natsumi、Hayasaka Yuto、Nakano Akihiko
  • Journal Title: Microbial Physiology Volume: 30 Issue: 1-6 Pages: 25-35
  • DOI: 10.1159/000509633
  • Peer Reviewed / Open Access
• [Journal Article] Runx1 and RORγt Cooperate to Upregulate IL-22 Expression in Th Cells through Its Distal Enhancer (2019)
  • Author(s): Sekimata Masayuki、Yoshida Daiki、Araki Akemi、Asao Hironobu、Iseki Ken、Murakami-Sekimata Akiko
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 11 Pages: 3198-3210
  • DOI: 10.4049/jimmunol.1800672
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cutting Edge: Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway (2019)
  • Author(s): Manabu Hayashi, Takeshi Machida, Yumi Ishida, Yusuke Ogata, Tomoko Omori, Mika Takasumi, Yuichi Endo, Toshiyuki Suzuki, Masayuki Sekimata, Yoshimi Homma, Masahito Ikawa, Hiromasa Ohira, Teizo Fujita, and Hideharu Sekine
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 6 Pages: 1411-1416
  • DOI: 10.4049/jimmunol.1900605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] マウス胎児顎下腺上皮細胞の無血清培養の試みにおける増殖因子と低分子化合物の検索 (2019)
  • Author(s): 関亦明子、推名裕美、牧野貴大、関亦正幸
  • Organizer: 第４２回日本分子生物学会年会、福岡