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Alternative Splicing Regulator RBM20 and Cardiomyopathy
Takeshi Watanabe1,2, Akinori Kimura3,4, Hidehito Kuroyanagi1,4,5
1Laboratory of Gene Expression, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Frontiers in Molecular Biosciences
|December 15, 2018
Summary
RNA-binding protein 20 (RBM20) regulates heart muscle splicing, particularly the TTN gene. Dysfunctional RBM20 impacts cardiac function, suggesting it as a therapeutic target for heart conditions like dilated cardiomyopathy.
Area of Science:
- Molecular Biology
- Cardiovascular Biology
- Genetics
Background:
- RNA-binding protein 20 (RBM20) is crucial for heart-specific alternative splicing.
- Mutations in RBM20 are linked to dilated cardiomyopathy (DCM).
- RBM20 regulates the alternative splicing of the TTN gene, encoding the giant protein titin.
Purpose of the Study:
- To investigate the role of RBM20 in regulating TTN splicing and its impact on cardiac passive stiffness.
- To explore RBM20 as a potential therapeutic target for diastolic dysfunction.
Main Methods:
- Analysis of RBM20's function in alternative splicing, particularly of the TTN gene.
- Investigation of RBM20's role in cardiac passive tension and diastolic function.
- Evaluation of therapeutic potential by manipulating TTN splicing in disease models.
Main Results:
- RBM20 represses over 160 consecutive exons of the TTN gene.
- RBM20-mediated TTN splicing is critical for cardiomyocyte passive stiffness and diastolic function.
- Modulating TTN splicing to increase titin compliance rescued phenotypes in diastolic dysfunction models.
Conclusions:
- RBM20 is a key regulator of TTN splicing, essential for normal heart diastolic function.
- Targeting RBM20 or TTN splicing presents a promising therapeutic strategy for diastolic heart failure.
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