Molecular mechanisms of non-coding genome regions causing age-dependent arrhythmia in human

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K21598
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Takeuchi Jun 東京医科歯科大学, 難治疾患研究所, 准教授 (10451999)
• Co-Investigator(Kenkyū-buntansha): 井原 健介 東京医科歯科大学, 難治疾患研究所, 助教 (50770210)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: 先天異常 / 心疾患 / Tbx5 / 非コードRNA / 肉腫化

Outline of Final Research Achievements

We are focusing on the epigenetic factors to understand the molecular mechanisms for the diversity of disease severity in heart-hand syndromes. In this project, we has reported 2 scientific papers, 1 review article, and 2 papers in submission over the past 3 years. 1) We found Gm5563;Tbx5 DKO embryos with the severe heart defects including hypoplastic ventricular structures during the heart formation. mRNAseq analysis from the heart tissues in these embryos revealed that the expression of genes function as key players for the ventricular muscle proliferation and formation was markedly suppressed. The results of ChIPseq and RIP-qPCR analysis revealed that the expression of the genes directly regulated the expression of cell growth factors by the synergistic function between Tbx5 and Gm5563. 2) We also reported that WNT-GPC5 signaling causes epigenetic modifications on Tbx5 locus to change the cell fate of sarcoma from that of mesenchymal stem cells.

Free Research Field

先天異常

Academic Significance and Societal Importance of the Research Achievements

ヒト先天異常症の重症化のメカニズムの理解は緩和治療・個別化医療を目指す上で不可欠である。本研究で明らかにされた非コードRNAは特異的な疾患責任遺伝子と相互作用し、下流標的遺伝子の発現制御を担っていることを明らかにしただけでなく、がん細胞など細胞性質をエピジェネティックに変化させる機能を持ち合わせていることも明らかにした。これらのことから、エピゲノム因子を用いた治療法の開発も期待される。