2021 Fiscal Year Final Research Report
Dissecting the cardiogenic network of ZNF281
| Project/Area Number |
19K17537
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 再生医療 / 心臓発生 / 心筋分化 / リプログラミング / 転写因子 |
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| Outline of Final Research Achievements |
During direct cardiac reprogramming, cardiogenic TFs cooperatively reshape the epigenomic landscape by activating cardiac enhancers, which describe a common epigenetic signature between in vitro cardiac reprogramming and in vivo heart development. We thus hypothesized that direct reprogramming could be a useful tool to study novel transcriptional regulators in heart development. To test this hypothesis, we focused on ZNF281, which showed up as an unexpected strong cardiac reprogramming inducer from our previous unbiased screen.
By using multiple genetic mouse models, we discovered that cardiac reprogramming inducer ZNF281 plays a pivotal role in heart development. We generated different stage-specific ZNF281KO mouse lines and found that mesodermal ZNF281KO mice were embryonic lethal as early as E9.5, associated with various cardiac anomalies. Our study demonstrates and highlights the impact and possibility of direct reprogramming as a novel approach to study cardiovascular biology.
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| Free Research Field |
再生医療
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| Academic Significance and Societal Importance of the Research Achievements |
心血管疾患は世界において死亡原因の第一位であり、その要因の一つは心臓に十分な自己再生能がない事である。また、心臓発生の転写制御ネットワークに関しては未だ不明な点が多く、現存する医療技術では未だに心臓を創り出し、有効に再生して修復する事ができていない。現在、心臓形成の分子機構を研究するにはヒトと同じ哺乳類であるマウスを用いることが主流であるが、多くの費用と時間を要する。このような中、我々は線維芽細胞から心筋細胞を直接誘導する分化転換法に着目し、細胞のみを用いるこの系が心臓発生の分子機構を研究する新たなツールとなりうることを科学的に立証した。
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