Elucidation of disease mechanism of LMNA-mutant dilated cardiomyopathy focusing on chromatin remodeling and DNA damage response

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17515
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ito Masamichi 東京大学, 医学部附属病院, 特任助教 (70794642)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 特発性拡張型心筋症 / iPS細胞 / LMNA変異 / 心不全

Outline of Final Research Achievements

In this study, in order to elucidate the pathogenesis of LMNA-mutated dilated cardiomyopathy, which has a poor prognosis and for which there is no cure, we generated iPS cells from the patients with LMNA mutation and differentiated them into cardiomyocytes. We found that LMNA mutant cardiomyocytes showed phenotypic abnormalities such as enhanced DNA damage response and abnormal electrical activity. Furthermore, comprehensive gene expression analysis of these cells showed decreased expression of muscle contractile fibers, suggesting impaired myocardial maturation. Furthermore, analysis of the epigenome, a regulatory system for gene expression, suggested that the expression of a group of target molecules of the transcription factor TEAD1 was reduced in LMNA-mutant myocardium. These findings may lead to understanding of the pathogenesis of DCM and the development of new therapies.

Free Research Field

循環器病学

Academic Significance and Societal Importance of the Research Achievements

我々はこれまでの先行研究で、DNA損傷蓄積と心機能低下の因果関係を示してきた。今回用いた患者由来iPS心筋細胞を用い、心筋細胞のDNA損傷を軽減する化合物をスクリーニングすることで新たなDCMの治療候補化合物を同定できる可能性がある。
また、今回の結果はTEAD1の標的遺伝子群の発現低下が心筋細胞の成熟化障害に関与している可能性を示唆しており、TEAD1遺伝子導入によって心筋細胞の成熟化誘導が可能であれば、心不全進行過程で見られる心筋細胞の幼若化を抑えることで、新しい心不全治療法を提唱できる可能性がある。