Unravelling the etiology of dilated cardiomyopathy through differential miRNA-mRNA interactome

Dilated cardiomyopathy (DCM) entails a broad group of diseases, acquired or genetic, that share a similar phenotype. The understanding of gene-specific pathogenetic mechanisms and the determination of the functional effects of each variant may tailor different therapeutic strategies. MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the development of several cardiovascular diseases, including DCM. Here, we applied mRNA and small RNA sequencing to identify the gene and miRNA signature from myocardial biopsies from four patients with DCM caused by volume overload (VCM) and four with ischemic DCM (ICM). Analysis showed five miRNAs and 112 mRNAs dysregulated in VCM vs ICM. Differentially expressed genes were positively enriched for extracellular matrix (ECM), mitochondria respiration-related, cardiac muscle contraction and fatty acid pathways in VCM vs ICM, and negatively enriched for immune response-related pathways, JAK-STAT and NF-kappa B signaling pathways in VCM vs ICM. miRNA-mRNA interaction analysis revealed four negatively correlated miRNA-target transcript pairs, miR-218-5p-DDX6, miR-218-5p-TT39C, miR-218-5p-SEMA4A and miR-494-3p-SGMS2. qRT-PCR validation showed a strong correlation between RNA-seq and qRT-PCR for these genes and miRNAs. These findings suggest that transcriptome signatures may distinguish distinct etiologies of DCM shedding light on underlying biological differences between VCM and ICM.