Converging pathways involving microRNA-206 and the RNA-binding protein KSRP control post-transcriptionally utrophin A expression in skeletal muscle

Abstract

Several reports have previously highlighted the potential role of miR-206 in the post-transcriptional downregulation of utrophin A in cultured cells. Along those lines, we recently identified K-homology splicing regulator protein (KSRP) as an important negative regulator in the post-transcriptional control of utrophin A in skeletal muscle. We sought to determine whether these two pathways act together to downregulate utrophin A expression in skeletal muscle. Surprisingly, we discovered that miR-206 overexpression in cultured cells and dystrophic muscle fibers causes upregulation of endogenous utrophin A levels. We further show that this upregulation of utrophin A results from the binding of miR-206 to conserved sites located in the 3′-UTR (untranslated region) of KSRP, thus causing the subsequent inhibition of KSRP expression. This miR-206-mediated decrease in KSRP levels leads, in turn, to an increase in the expression of utrophin A due to a reduction in the activity of this destabilizing RNA-binding protein. Our work shows that miR-206 can oscillate between direct repression of utrophin A expression via its 3′-UTR and activation of its expression through decreased availability of KSRP and interactions with AU-rich elements located within the 3′-UTR of utrophin A. Our study thus reveals that two apparent negative post-transcriptional pathways can act distinctively as molecular switches causing repression or activation of utrophin A expression.

MiR-206, a Key Modulator of Skeletal Muscle Development and Disease

“…MiR-206 is a member of the miR-1 family, and the gene for miR-206 is located between the interleukin-17 gene and the polycystic kidney and hepatic disease 1 gene in human (chr 6), mouse (chr 1) and rat (chr 9), and their sequences are highly conserved 14 , 15 . MiR-1-1 and miR-1-2 share an identical nucleotide sequence, while the sequence of miR-206 differs from miR-1-1 and miR-1-2 by four nucleotides outside of the seed region.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…Factors KSRP [35] , MBNL1 and RNA binding protein LIN28 [36] also positively and negatively regulate miR1 biogenesis respectively. Additionally, miR206 binds to 3'UTR sites of KSRP transcript to inhibit KSRP expression in skeletal muscle [37] . Independently, miR206 and KSRP are negative regulators of utrophin A, but unexpectedly, overexpression of miR206 in both normal and dystrophic muscle cells promotes upregulation of utrophin A, via the downregulation of KSRP.…”

The long and short of non-coding RNAs during post-natal growth and differentiation of skeletal muscles: Focus on lncRNA and miRNAs

“…Utrn shows a similar pattern of mRNA regulation to Agrn, and both of these proteins are indicators of NMJ maturation during the first 3 weeks of post-natal growth. There is complex regulation of Utrn expression by miR-206, that can either repress or activate Utrn (Amirouche et al, 2013), therefore as miR-206 levels decrease after 2 weeks, Utrn RNA levels remain stable, allowing for the consistent expression of this functional protein.…”