A Proposed Model of Alternative Splicing of Cyclin-Dependent Kinase 8 Underlying Mechanisms of Heart Failure Secondary To Hypertension.

The regulation of eukaryotic gene expression is a multifacted system in which both gene transcription and post transcriptional modifications play a crucial role in maintaining proper gene expression. The Mediator complex and its associated proteins are integral in the enhancer-driven gene expression with previous literature investigating the potential connections between disrupted Mediator complex function and neurological, cardiovascular, and developmental disease states. Another well-understood mechanism regulating eukaryotic protein expression is alternative splicing of mRNA transcripts, generating protein diversity from a single gene. Alternative splicing is thought to contribute to cellular differentiation and developmental processes and is associated with human disease and cancer. Therefore, the discovery of alternative splicing events in critical genes within essential complexes, like the Mediator complex, may grant better understanding of human disease, and thus lead to better treatments and health outcomes. In this study, we identified alternative splice sites within the mediator complex through RNAseq analysis of murine Sham and Trans-aortic banding ventricular lysates. We also identified alternative splice sites within the mediator complex when comparing human ventricular cardiomyocyte RNA-seq between healthy and decompensated heart failure patients secondary to pulmonary hypertension. Our findings display significant changes in alternative splicing of CDK8 transcripts in models of cardiovascular disease in murine and human samples. This finding implicates the alternative splicing of CDK8 kinase domain as a regulatory mechanism underlying gene expression changes in heart failure.