Deciphering the Molecular Mechanism of Incurable Muscle Disease by a Novel Method for the Interpretation of miRNA Dysregulation

Abstract

It is now well-established that microRNA dysregulation is a hallmark of human diseases, and that aberrant expression of miRNA is not randomly associated with human pathologies but plays a causal role in the pathological process. Investigations of the molecular mechanism that links miRNA dysregulation to pathophysiology can therefore further the understanding of human diseases. The biological effect of miRNA is thought to be mediated principally by miRNA target genes. Consequently, the target genes of dysregulated miRNA serve as a proxy for the biological interpretation of miRNA dysregulation, which is performed by target gene pathway enrichment analysis. However, this method unfortunately often fails to provide testable hypotheses concerning disease mechanisms. In this paper, we describe a method for the interpretation of miRNA dysregulation, which is based on miRNA host genes rather than target genes. Using this approach, we have recently identified the perturbations of lipid metabolism, and cholesterol in particular, in Duchenne muscular dystrophy (DMD). The host gene-based interpretation of miRNA dysregulation therefore represents an attractive alternative method for the biological interpretation of miRNA dysregulation.