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BET Protein Regulation of Myocardial Injury and SARS-CoV-2 Infection


A common paradigm seen across diverse cell types in development, tissue homeostasis, and disease is the role of protein interactions in regulating essential cellular processes. Mounting the appropriate biological response to physiologic or pathologic stressors is critical for organismal survival. Mechanisms of transcriptional regulation have been extensively studied in eukaryotic organisms, which have shed light on how organisms dynamically assemble transcriptional complexes on chromatin to drive cell-type specific gene expression. These transcriptional responses can be beneficial, such as those observed in rapidly activated antiviral responses upon infection of host cells. However, prolonged or inappropriate activation of these expression programs may contribute to disease, as has been seen in some cancers and cardiovascular diseases. My dissertation explores the role of a particular class of transcriptional regulators, the Bromodomain and Extra-Terminal (BET) family of acetyl-lysine reader proteins. Through unique protein interactions mediated by their bromodomains, which bind to acetylated proteins, I show that BET chromatin factors are central in regulating dynamic transcriptional responses across two distinct pathologies using in vitro and in vivo model systems. First, I describe how BET proteins act as transcriptional coactivators promoting inflammatory and fibrotic processes in heart failure pathogenesis with mechanistic insights and therapeutic implications for targeting this class of proteins. Second, I present data describing how BET proteins act as important inhibitory factors in response to SARS-CoV-2 infection to which viral factors have evolved mechanisms to disrupt. Collectively, these findings advance our understanding on the diverse roles of BET proteins in disease, which will ultimately inform important considerations in the potential to therapeutically target these factors.

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