Advisory Committee Chair
Martin E Young
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Rationale: Cardiovascular disease continues to be the leading cause of death in America. Many aspects of both cardiovascular physiology (e.g., blood pressure, heart rate) and pathophysiology (e.g., myocardial infarctions, sudden cardiac death) exhibit time-of-day dependent fluctuations (termed diurnal variations). Circadian clocks consist of transcriptional feedback cascades directly modulating expression of genes involved in processes such as metabolism, signaling, and ion transport. Interestingly, genetic deletion of a core circadian clock component in the heart (cardiomyocyte-specific Bmal1 knockout mice) leads to chronic induction of the transcriptional repressor E4 Promoter-Binding Protein 4 (E4BP4) associated with early-onset dilated cardiomyopathy, metabolic inflexibility, and electrophysiologic disturbances. There is also evidence that small RNA species exhibit time-of-day dependent expression: microRNAs (miRNAs) are a specific type of small RNA species which mediate post-transcriptional regulation of mRNAs, impacting various cellular processes. The exact mechanisms by which circadian clocks regulate cardiac physiology remains less clear. These observations have led to the hypothesis that the CCC regulates important physiologic processes through E4BP4 and miRNAs. Methods & Results: If the cardiomyocyte circadian clock (CCC) regulates physiologic processes through E4BP4, then RNA sequencing will facilitate determining the genomewide effects of deletion of E4BP4. Transcriptomic analysis revealed that deletion of E4BP4 iv leads to differential expression of mRNAs involved in metabolism, signaling, and ion transport. Consequently, we performed electrocardiogram (ECG) telemetry experiments to determine if genetic modulation of E4BP4 expression affects ECG parameters. We found that there is a direct correlation of E4BP4 expression level and QT interval length. If the CCC regulates important physiologic processes through miRNAs, then small RNA sequencing will facilitate identifying these relationships. Transcriptomics analysis revealed that BMAL1 deletion leads to differential expression of 47 miRNAs. With integrative omics analysis, we were able to identify putative connections between BMAL1 and transcriptional regulators (e.g., REV-ERBα/β) of differentially expressed miRNAs (e.g., let-7c-1-3p, miR-215-5p, and miR-23b-5p). These miRNAs targeted mRNAs associated with pathways involved in circadian rhythms, signaling, and metabolism. Conclusions: This dissertation provides evidence that E4BP4 regulates cardiac ventricular repolarization (represented by the QT interval) and miRNAs may link the cardiomyocyte circadian clock to cardiac processes like signaling and metabolism.
Williams, Lamario J., "Mechanisms Linking the Circadian Clock to Cardiac Physiology" (2023). All ETDs from UAB. 366.