MBNL expression in autoregulatory feedback loops

RNA Biol. 2018 Jan 2;15(1):1-8. doi: 10.1080/15476286.2017.1384119. Epub 2017 Nov 13.

Abstract

Muscleblind-like (MBNL) proteins bind to hundreds of pre- and mature mRNAs to regulate their alternative splicing, alternative polyadenylation, stability and subcellular localization. Once MBNLs are withheld from transcript regulation, cellular machineries generate products inapt for precise embryonal/adult developmental tasks and myotonic dystrophy, a devastating multi-systemic genetic disorder, develops. We have recently demonstrated that all three MBNL paralogs are capable of fine-tuning cellular content of one of the three MBNL paralogs, MBNL1, by binding to the first coding exon (e1) of its pre-mRNA. Intriguingly, this autoregulatory feedback loop grounded on alternative splicing of e1 appears to play a crucial role in delaying the onset of myotonic dystrophy. Here, we describe this process in the context of other autoregulatory and regulatory loops that maintain the content and diverse functions of MBNL proteins at optimal level in health and disease, thus supporting the overall cellular homeostasis.

Keywords: Alternative splicing; MBNL1; RBFOX; autoregulation; feedback loop; muscleblind-like; myotonic dystrophy; therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Exons / genetics
  • Feedback, Physiological
  • Gene Expression Regulation, Developmental
  • Humans
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / pathology
  • Polyadenylation / genetics
  • Protein Binding
  • RNA Precursors / genetics
  • RNA Splicing Factors / genetics
  • RNA-Binding Proteins / genetics*

Substances

  • MBNL1 protein, human
  • RBFOX1 protein, human
  • RNA Precursors
  • RNA Splicing Factors
  • RNA-Binding Proteins

Grants and funding

This work was supported by the Foundation for Polish Science-TEAM program cofinanced by the European Union within the European Regional Development Fund (to K.S.); the National Centre for Research and Development under Grant ERA-NET-E-Rare-2/III/DRUG_FXSPREMUT/01/2016 (to K.S.); the Polish National Science Centre Grants 2014/15/B/NZ5/00142 (to E.S.-K.) and 2014/15/B/NZ2/02453 (to K.S); and the Ministry of Science and Higher Education of the Republic of Poland, from the quality-promoting subsidy, under the Leading National Research Centre (KNOW) program for the years 2012–2017 [KNOW RNA Research Centre in Poznan (No. 01/KNOW2/2014)].