A Yap to Notch Transcriptional Activity Transition Governs Postnatal Cardiomyocyte Maturation

PROJECT SUMMARY Heart failure is the leading cause of morbidity and mortality in the United States, with many heart failure cases being the result of an ischemic insult such as coronary artery disease or myocardial infarction. As the adult heart lacks native regenerative repair mechanisms, most current heart failure therapies attempt to alleviate patient’s symptoms. However, recent studies have demonstrated that mammals do have endogenous cardiac repair mechanisms in early postnatal stages, but this endogenous regenerative ability wanes as postnatal maturation proceeds. This regenerative ability is lost as cardiomyocyte proliferation naturally decreases throughout cardiomyocyte maturation, as cardiomyocytes need to switch from hyperplastic growth to hypertrophic growth to adjust to the demands of pumping blood throughout the body. This switch to hypertrophic growth is accompanied by metabolic and sarcomere state changes, however the mechanistic underpinnings of these cardiomyocyte maturation changes are well characterized. Initial mechanistic examinations of cardiomyocyte maturation identified the Hippo signaling pathway due to how Hippo signaling could promote or inhibit CM proliferation depending on the activity of its transcriptional effector Yap1. My transcriptional activity analysis discovered major transcriptional landscape changes between induced-immature cardiomyocytes and controls, with high Yap activity defining immature cardiomyocytes while Notch activity defined mature cardiomyocytes. Interestingly, transitions between Yap and Notch activity are critical to cell type or state changes in various organ systems, however whether a Yap to Notch transition regulates cardiomyocyte maturation has not been investigated. Thus, I hypothesize that Notch activity is critical to promote and maintain mature cardiomyocytes, with a Yap to Notch transcriptional activity transition regulating cardiomyocyte maturation state. To address this hypothesis, I will utilize genomic techniques alongside mouse models to examine cardiomyocyte maturation in vivo. My first aim will define the role of Notch transcriptional activity in postnatal cardiomyocyte maturation state, defining whether Notch maintains a mature cardiomyocyte state (1A), is necessary for transition to a mature cardiomyocyte state (1B), or directly promotes a mature cardiomyocyte state (1C). As our preliminary data demonstrates a transition between Yap and Notch coinciding with cardiomyocyte maturation state, aim 2 will address possible mechanisms underlying the endogenous switch from Yap to Notch activity during postnatal maturation. First investigating how Yap activity may directly promote a transition to a Notch active state (2A), alongside how Notch activity may directly inhibit Yap activity to facilitate cardiomyocyte maturation (2B). In total, the proposed project aims would further our understanding of cardiomyocyte maturation along with the transcriptional regulatory programs that govern cardiomyocyte maturation. Providing knowledge that could be utilized to improve regenerative therapeutic development for heart failure.