Integrated analysis of miRNA-mRNA interaction in pediatric dilated cardiomyopathy

Background: MicroRNAs (miRNAs) are short single-stranded nucleotides that can regulate gene expression. Although we previously evaluated the expression of miRNAs in pediatric dilated cardiomyopathy (DCM) by miRNA array, pathway prediction based on changes in mRNA expression has not been previously analyzed in this population. The current study aimed to determine the regulation of miRNA expression by miRNA-sequencing (miRNA-seq) and, through miRNA-sequencing (mRNA-seq), analyze their putative target genes and altered pathways in pediatric DCM hearts.

Methods: miRNA expression was determined by miRNA-seq [n = 10 non-failing (NF), n = 20 DCM]. Expression of a subset of miRNAs was evaluated in adult DCM patients (n = 11 NF, n = 13 DCM). miRNA-mRNA prediction analysis was performed using mRNA-seq data (n = 7 NF, n = 7 DCM) from matched samples.

Results: Expression of 393 miRNAs was significantly different (p < 0.05) in pediatric DCM patients compared to NF controls. TargetScan-based miRNA-mRNA analysis revealed 808 significantly inversely expressed genes. Functional analysis suggests upregulated pathways related to the regulation of stem cell differentiation and cardiac muscle contraction, and downregulated pathways related to the regulation of protein phosphorylation, signal transduction, and cell communication.

Conclusions: Our results demonstrated a unique age-dependent regulation of miRNAs and their putative target genes, which may contribute to distinctive phenotypic characteristics of DCM in children.

Impact: This is the first study to compare miRNA expression in the heart of pediatric DCM patients to age-matched healthy controls by RNA sequencing. Expression of a subset of miRNAs is uniquely dysregulated in children. Using mRNA-seq and miRNA-seq from matched samples, target prediction was performed. This study underscores the importance of pediatric-focused studies.