Characterisation of lnc-G4, a long noncoding RNA that regulates skeletal muscle differentiation through translational repression of G-quadruplex containing mRNAs

Long non-coding RNAs are crucial regulators of the fine tuning of gene expression. Their role has been widely studied especially in developmental processes such as skeletal muscle differentiation. In particular, a novel cytoplasmic long non-coding RNA, called lnc- G4, has a relevant role in promoting murine C2C12 myoblast differentiation. The analysis of the interactors of this long non- coding RNA showed its ability to base-pair with many mRNAs thanks to a repeated element embedded in its sequence; among the interactors, we focused on MLX mRNA, which encodes for a myogenic transcription factor. We demonstrated that lnc-G4 directly interacts with the three splicing isoforms of MLX mRNA, while it is able to specifically inhibit the translation of only MLX g isoform; this translational regulation could depend on the recruitment of the RNA helicase DHX36. Interestingly, the effect of lnc-G4 on MLX g regulates the subcellular localization of the other isoforms, and this has an impact on the transcriptional activation of MLX targets. Taken together, these evidences suggest that lnc-G4 could be a key factor in post-transcriptional gene regulation during the early phases of myogenesis through the translational regulation of MLX g. Moreover, lnc-G4 interacts with other mRNAs, and the regulation mechanism could be extended to many other targets.