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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE300969 | GEO | 2026/08/01

REPOSITORIES: GEO

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Project description:There is an unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545 a WNT-pathway inhibitor discovered by cell-based screening is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19 CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours. Compound 1,2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site. A 3D culture model of murine intestinal-derived organoids expressing a transgenic doxycycline-inducible mutant beta-catenin expression following removal of doxycycline results in reduced WNT signalling and was compared to treatment for 24 hours with coumpound 2, 6 and 9. Compound 2 (n=3), compound 6 (n=4), compound 9 (n=3), doxycycline removal (n=4), doxycycline treatment (n=7). Samples were hybridized agianst mouse reference. Compounds 2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.

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

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