Project Summary Heart failure (HF) is associated with a 5-year mortality of 50% and the incidence is still rising. Identifying novel strategies to HF is of urgent clinical need. One missed opportunity is that HF is associated with a stereotypical gene expression program, however, the current therapy focuses on improving hemodynamics and neurohormonal milieu, the already committed gene program is not reversed. We have identified a circadian repressor REV-ERBα, which binds near pathological driver transcription factor MEF2s in the heart and prevents pathological gene program activation during HF. We demonstrated that pharmacological agonist of REV-ERBα ameliorates cardiac hypertrophy and HF during a variety of stresses both as prevention and as late disease stabilization. Cardiac deletion of REV-ERBα and b leads to exaggerated heart failure after pressure overload and spontaneously with aging. Further, we found REV-ERBα agonist has a similar effect in human induced pluripotent stem cells derived cardiomyocytes. We thus hypothesize that REV-ERBα inhibits cardiac pathological remodeling through transcriptional repression at the aberrantly activated MEF2 enhancers. Our long-term goal is to understand how REV-ERBα inhibits gene program in the cardiomyocytes and develop REV-ERBα enhancement as a novel therapeutic strategy for HF. In this proposal, we have two specific aims towards this goal: (1) define the role of REV-ERB in the cardiomyocytes at rest and under cardiac stress; (2) determine the molecular basis of REV-ERBα and MEF2c interaction during cardiac remodeling. Completion of this proposal will have significant impact in understanding gene regulation in the heart during pathological remodeling and potentially expand our therapeutic strategies for HF treatment.