Locking and Unlocking Cardiac Maturation

SUMMARY Significant progress has been made in defining the events involved in early cardiac development. Much less is known about the developmental maturation process that begins in late fetal stages and proceeds into the postnatal period, resulting in the terminally differentiated adult heart. Deciphering the regulatory mechanisms involved in cardiac maturation has important translational relevance for understanding the genetic origins of heart disease, development of new therapeutics for heart failure, and optimizing cardiomyocyte (CM) regeneration strategies. The new directions outlined in this R35 proposal stem from a series of discoveries in my laboratory, supported by continuous NHLBI funding since 1998, that defined a transcriptional regulatory circuitry that is critical for cardiac maturation. We have found that the orphan nuclear receptor estrogen-related receptor (ERR) and its coactivator PPARγ coactivator 1 (PGC-1) are critical for the coordinate regulation of mitochondrial and contractile processes during cardiac maturation, and in the adult heart. Genomic interrogation studies have defined the gene annotated ERR cistrome in human cardiomyocytes (CMs) demonstrating that this transcription factor occupies over 50% of super-enhancers, often in close proximity and cooperation with the cardiogenic transcription factor GATA4. These findings provide an opportunity to address several conceptual gaps and bold questions that form the basis for the proposed R35 project: 1) Do naturally-occurring variants in human CM genomic ERR binding sites contribute to genetic and acquired forms of heart disease?; 2) What is the impact of maintaining or reactivating the adult CM maturation program in the failing heart?; and 3) Conversely, can components of the adult CM maturation program be transiently “unlocked” to enable CM proliferation? To address these questions, we will identify and characterize common and rare variants in human CM ERR binding sites associated with congenital heart disease and cardiomyopathy, assess the potential of maintaining or re-activating the transcriptional control of CM maturation as a novel therapeutic strategy for heart failure, and assess targeting the ERR/PGC-1 circuitry to unlock metabolic maturation as a strategy to transiently enable CM regeneration. This project represents a new avenue that has emerged from years of productive research supported by continuous NHLBI R01 funding. The proposed studies show promise for high impact translational breakthroughs including defining the importance of non-coding DNA variants as drivers or modifiers of heart disease - a strategy that can be extended to non-cardiac diseases, optimization of hiPSC-CM maturation by targeting the PGC-1/ERR circuit, re-activation of CM maturation as a potential novel therapeutic approach for heart failure, and the bold goal of transiently enabling CM regeneration.