ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Biol Chem. 2018; 293(6): 1865-1874

MicroRNAs (miRNAs) are short RNA species, generally 19–22 nucleotides in length, which mediate post-transcriptional down-regulation of protein expression (28). Given that miRNAs exert such pervasive effects on biological processes, it is not surprising that they have an effect on GC action at several points. Their touch is often light, in the sense that individual miRNAs alter expression of their targets only modestly. Nevertheless, each miRNA can hit several targets, and each target may be hit by several different miRNAs. Therefore, coherent and coordinated changes of miRNA abundance can affect complex biological processes profoundly. Furthermore, functional interactions between miRNAs and target transcripts are based on limited sequence complementarity. Such regulatory complexity creates two sets of major challenges. The first are essentially challenges of methodology and bio-informatics. These challenges are increasingly being met through improvements in miRNA target prediction algorithms, systems biological approaches, better methodologies, and more widespread adoption of best-practice experimental controls. The second set of challenges relate to the therapeutic exploitation of knowledge gained. In this context, advances are likely to be most rapid in situations where insensitivity to GCs is a pressing clinical problem, for example in hematological malignancies and GC- resistant asthma. Even where good therapeutic targets can be clearly identified, it remains to be seen whether a mimic or antagonist of a single miRNA species will be sufficient to exert therapeutic effects. If targeting more than one miRNA proves necessary, this will create additional barriers to development, in part because of the problem of predicting and mitigating off- target effects. This field of endeavour is an exciting one, but success is far from certain.

28. Filipowicz W, Bhattacharyya S N, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 2008; 9, 102–114.