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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00649

Global increase in circRNA levels in myotonic dystrophy

 Karol Czubak1, Katarzyna Taylor2, Agnieszka Piasecka2, Krzysztof Sobczak2,  Katarzyna Kozłowska1, Anna Philips1,  Saam Sedehizadeh3,  John D. Brook3, Marzena Wojciechowska1, 3 and  Kozlowski Piotr1*
  • 1Institute of Bioorganic Chemistry (PAS), Poland
  • 2Adam Mickiewicz University in Poznań, Poland
  • 3University of Nottingham, United Kingdom

Splicing aberrations induced as a consequence of the sequestration of MBNL splicing factors on the DMPK transcript, which contains expanded CUG repeats, present a major pathomechanism of myotonic dystrophy type 1 (DM1). As MBNLs may also be important factors involved in the biogenesis of circular RNAs (circRNAs), we hypothesized that the level of circRNAs would be decreased in DM1. To test this hypothesis, we selected twenty well-validated circRNAs and analyzed their levels in several experimental systems (e.g., cell lines, DM muscle tissues, and a mouse model of DM1) using droplet digital PCR assays. We also explored the global level of circRNAs using two RNA-Seq datasets of DM1 muscle samples. Contrary to our original hypothesis, our results consistently showed a global increase in circRNA levels in DM1 and we identified numerous circRNAs that were increased in DM1. We also identified many genes (including muscle-specific genes) giving rise to numerous (>10) circRNAs. Thus, this study is the first to show an increase in global circRNA levels in DM1. We also provided preliminary results showing the association of circRNA level with muscle weakness and alternative splicing changes that are biomarkers of DM1 severity.

Keywords: circular RNAs (circRNAs), Myotonic dystrophy type 1 (DM1), circRNA biogenesis, CIRI2, Droplet digital PCR (ddPCR), DM1 biomarkers

Received: 21 Feb 2019; Accepted: 19 Jun 2019.

Edited by:

Rosanna Asselta, Humanitas University, Italy

Reviewed by:

Andy Berglund, RNA Institute, College of Arts and Science, University at Albany, United States
Alessandra Perfetti, Policlinico San Donato (IRCCS), Italy  

Copyright: © 2019 Czubak, Taylor, Piasecka, Sobczak, Kozłowska, Philips, Sedehizadeh, Brook, Wojciechowska and Piotr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Kozlowski Piotr, Institute of Bioorganic Chemistry (PAS), Poznań, 61-704, Greater Poland, Poland, kozlowp@ibch.poznan.pl