Control of muscle differentiation in normal and pathological condition: the role of dystrophin and non coding RNAs

Muscle differentiation is an excellent system to study the mechanisms of transcriptional and post-transcriptional gene regulation in vertebrates. A regulatory circuitry in which competing endogenous RNAs (ceRNAs) act as a sponges to micro-RNAs was first demonstrated in in-vitro mouse myoblast differentiation for the muscle specific pro-myogenic long non coding RNA, linc-MD1. Here we characterized linc-hMD1, the human homologue of murine linc-MD1. We demonstrated that linc-hMD1 is down regulated in Dunchenne Muscular Dystrophy (DMD) myoblast and it is rescued towards wild type levels in exon skipping treated cells. We showed that it can act as a sponge for miR-133. One of the interesting features of linc-hMD1 is that it is also the host transcript for miR-133b and the biogenesis of these two non-coding RNAs is mutually exclusive. Towards this we showed that the alternative biogenesis of linc-hMD1 and miR-133b is regulated post transcriptionally through binding of HuR protein to pri-linc-hMD1 transcript. We studied the physiological relevance of this regulatory circuitry in human myoblast differentiation and showed that sponging activity of linc-hMD1 occurs during early stages of differentiation while at later stages,linc-hMD1 acts as a precursor for miR-133b.