THE ROLE OF HETEROCHROMATIN PROTEIN 1 BINDING PARTNER 3, HP1BP3, IN THE CARDIOMYOCTYE STRESS RESPONSE USING THE MURINE MODEL OF PRESSURE OVERLOAD

Abstract

An epigenetic protein Heterochromatin Protein 1 Binding Partner 3, HP1BP3, was uncovered through single nuclear sequencing of healthy and diseased CMs. It is centrally located within a network of disease-related cardiac genes, suggesting its role in disease gene regulation. It is up-regulated in a sub-population of diseased CMs, but its differential expression is masked in bulk cardiac tissue. Therefore, to investigate its role in regulating cardiomyocyte stress genes, a series of in vitro knockdown (KD) and over-expression experiments were first performed and then brought forth to in vivo using a unique cardiomyocyte-specific, cardiotrophic rAAV9-mediated KD technique. In vitro results showed changes in apoptosis and stress genes regulation while in vivo results showed maintenance of heart function through Hp1bp3-KD cardiomyocytes that were hypertrophic and hypercontractile. The thesis also covers an in-depth investigation of the mouse model of pressure overload that is ubiquitously used for studying cardiac hypertrophy and heart failure.