Non-coding RNAs in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and impaired systolic function. Progression of the disease leads to heart failure, a state in which the heart is unable to pump sufficient blood to meet the body's metabolic demands. While DCM is often familial and linked to genetic mutations, causative variants are identified in only 30–40% of cases, primarily in protein-coding genes. Given that only 2% of the human genome encodes protein, it is likely that mutations in non-coding regions explain some of the unresolved cases.
This thesis investigates the contribution of two classes of non-coding RNAs to DCM pathogenesis. In the first part we focus on microRNAs (miRNAs), ~22 nucleotide long RNAs molecules that regulate gene expression by inhibiting messenger RNA translation. We screened DCM patients for variants in miRNAs implicated in cardiac contractility and identified two variants that alter the precursor miRNA secondary structure. This resulted in reduced miRNA expression and function, potentially contributing to the DCM phenotype in these individuals.
The second part explores circular RNAs (circRNAs), covalently closed RNA loops generated by back-splicing. We identified thousands of circRNAs in the human heart, several of which are dysregulated in DCM. Titin, which encodes the largest human transcript, generates the most circRNAs. We show that these TTN-derived circRNAs regulate expression and splicing of key cardiac genes, and that loss of the most abundant TTN-derived circRNA disrupts sarcomere organization and reduces contractility in vitro. Finally, we report a circRNA derived from a well-known cardiac gene as a novel biomarker for heart failure.