Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans

Lena Qawasmi, Maya Braun, Irene Guberman, Emiliano Cohen, Lamis Naddaf, Anna Mellul, Olli Matilainen, Noa Roitenberg, Danielle Share, Doron Stupp, Haya Chahine, Ehud Cohen, Susana M.D.A. Garcia*, Yuval Tabach

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

8 Scopus citations

Abstract

Myotonic dystrophy type 1 is an autosomal-dominant inherited disorder caused by the expansion of CTG repeats in the 3′ untranslated region of the DMPK gene. The RNAs bearing these expanded repeats have a range of toxic effects. Here we provide evidence from a Caenorhabditis elegans myotonic dystrophy type 1 model that the RNA interference (RNAi) machinery plays a key role in causing RNA toxicity and disease phenotypes. We show that the expanded repeats systematically affect a range of endogenous genes bearing short non-pathogenic repeats and that this mechanism is dependent on the small RNA pathway. Conversely, by perturbating the RNA interference machinery, we reversed the RNA toxicity effect and reduced the disease pathogenesis. Our results unveil a role for RNA repeats as templates (based on sequence homology) for moderate but constant gene silencing. Such a silencing effect affects the cell steady state over time, with diverse impacts depending on tissue, developmental stage, and the type of repeat. Importantly, such a mechanism may be common among repeats and similar in human cells with different expanded repeat diseases.

Original languageAmerican English
Pages (from-to)1711-1728
Number of pages18
JournalJournal of Molecular Biology
Volume431
Issue number9
DOIs
StatePublished - 19 Apr 2019

Bibliographical note

Funding Information:
We would like thank the BIRAX, the Institute for Medical Research Israel-Canada and the Academy of Finland for their generous support to our project. Orion foundation for the prusiner-abramsky research award. We would also like to thank Dr. Julie M. Claycomb at the Department of Molecular Genetics, University of Toronto and her research group, especially Dr. Monica Wu and Uri Seroussi, for their insight on small RNA pathways and their expertise with IP techniques. Prof. Millet Treinin at the Department of Medical Neurobiology, Hebrew University -Hadassah Medical School for her assistance and support. as well as Ayman Qawasmi and Nitzan Guberman for their help in graphical abstract design and assistance in the GFP fluorescence analysis respectively.

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • C. elegans
  • RNA interference
  • RNA toxicity
  • myotonic dystrophy
  • trinucleotide repeat disorders

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