Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR⁻target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.