Evolving systems biology approaches to understanding non-coding RNAs in pulmonary hypertension

Abstract

Our appreciation of the roles of non-coding RNAs, in particular microRNAs, in the manifestation of pulmonary hypertension (PH) has advanced considerably over the past decade. Comprised of small nucleotide sequences, microRNAs have demonstrated critical and broad regulatory roles in the pathogenesis of PH via the direct binding to messenger RNA transcripts for degradation or inhibition of translation, thereby exerting a profound influence on cellular activity. Yet, as inherently pleiotropic molecules, microRNAs have been difficult to study using traditional, reductionist approaches alone. With the advent of high-throughput -omics technologies and more advanced computational modelling, the study of microRNAs and their multi-faceted and complex functions in human disease serves as a fertile platform for the application of systems biology methodologies in combination with traditional experimental techniques. Here, we offer our viewpoint of past successes of systems biology in elucidating the otherwise hidden actions of microRNAs in PH, as well as areas for future development to integrate these strategies into the discovery of RNA pathobiology in this disease. We contend that such successful applications of systems biology in elucidating the functional architecture of microRNA regulation will further reveal the molecular mechanisms of disease, while simultaneously revealing potential diagnostic and therapeutic strategies in disease amelioration.

Keywords: microRNA; non-coding RNA; pulmonary hypertension; systems biology.

Figure 1. Application of systems biology in the elucidation of RNA biology in pulmonary hypertension

The advent of –omics‐based technologies has offered a new‐found opportunity to elucidate the complexity of human diseases such as PH. Non‐coding RNAs, such as microRNAs, have been identified as central biological mediators in the root cause of this disease. Accordingly, the successful application of systems biology and network theory in the interpretation of these coding and non‐coding RNA datasets will strive to produce insight into the functional behaviour of non‐coding RNAs across networks of genes, tissues and diseases related to the PH pathophenotype(s). Computational simulation and subsequent experimental validation will provide the substrate from which a ‘microRNA‐specific, precision medicine’ approach may begin to be conceptualized, if specific challenges of implementation can be overcome.