Transcriptome reprogramming is a key process of pathological remodeling in heart. In mammalian transcriptome, a significant portion of the genes produce more than one transcript species due to alternative RNA splicing. However, the contribution of alternative RNA splicing to total transcriptome complexity and its regulatory mechanism in heart failure is still poorly understood and understudied. Based on RNA sequencing and extensive validation studies, we have discovered that global pattern of alternative RNA splicing adapts a fetal-like profile in diseased hearts, including a highly conserved mutually exclusive splicing for all members of the transcriptional factor Mef2 family, Mef2a, Mef2c and Mef2d. We further find that Fox1 is a muscle enriched trans-acting RNA splicing factor that regulates this specific Mef2 splicing event in heart, producing splicing variants with distinct transcriptional activities and different functional impact in heart. Fox1 expression is diminished in mouse and human failing hearts. Inactivation of Fox1 in zebrafish causes developmental defects and cardiac dysfunction. Most remarkably, restoring Fox1 expression in mice significantly attenuates cardiac hypertrophy and dysfunction induced by pressure-overload. Therefore, alternative RNA splicing is a highly regulated process that significantly contributes to the transcriptome programming in heart. It has an important and previously underappreciated impact on cardiac development and pathogenesis. These exciting new findings lead to our current hypothesis that Fox1-MEF2 is a novel regulatory circuit in cardiac transcriptional network with a pivotal role in heart failure. In this proposal, we will expore this novel hypothesis at molecular and functional levels in multiple model systems in order to fully establish the underling mechanism and the functional importance of Fox-1 mediated RNA splicing regulation in heart failure. More specifically, we plan to accomplish in Aim 1: to determine the specific contribution of Fox-1 to transcriptome complexity in cardiomyocytes;
in Aim 2 : to investigate the molecular basis and functional impact of Mef2a splicing variants in heart;
in Aim 3 : to establish the functional impact of Fox-1-Mef2 circuit in cardiac hypertrophy and heart failure. These studies will provide exciting new insights to cardiac transcriptome regulation in normal development and diseases, and promising new targets for therapeutic development.

Public Health Relevance

Heart failure is associated with changes in gene expression at a global level and its regulation is complex and important. Our proposal will investigate a newly discovered RNA splicing factor Fox1 in heart and aims to establish the molecular basis to its function in normal development and pathology. Since loss of Fox1 expression is associated and sufficient to cause heart failure, restoring its expression is a promising new strategy to treat an reverse the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122737-04
Application #
9247824
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Rosa-Garrido, Manuel; Chapski, Douglas J; Schmitt, Anthony D et al. (2017) High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure. Circulation 136:1613-1625
Gao, Chen; Howard-Quijano, Kimberly; Rau, Christoph et al. (2017) Inflammatory and apoptotic remodeling in autonomic nervous system following myocardial infarction. PLoS One 12:e0177750
Gao, Chen; Wang, Yibin (2017) Untangle a Broken Heart via Janus Kinase 1. Circ Res 121:589-590
Touma, Marlin; Kang, Xuedong; Zhao, Yan et al. (2016) Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery. Circ Cardiovasc Genet 9:395-407
Wang, Jessica J; Aboulhosn, Jamil A; Hofer, Ira S et al. (2016) Operationalizing Precision Cardiovascular Medicine: Three Innovations. Circ Res 119:984-987
Iorga, Andrea; Li, Jingyuan; Sharma, Salil et al. (2016) Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy. J Am Heart Assoc 5:
Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao et al. (2016) The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22:1131-1139
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Gao, Chen; Wang, Yibin (2016) Positive Role for a Negative Calcineurin Regulator in Cardiac Hypertrophy. Hypertension 67:841-2
Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung et al. (2016) RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J Clin Invest 126:195-206

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