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Title

Expanded CTG repeats trigger miRNA alterations in Drosophila that are conserved in myotonic dystrophy type 1 patients

AuthorsFernández-Costa, Juan M.; García López, A.; Zúñiga, Sheila; Fernández-Pedrosa, Victoria; Felipo-Benavent, Amelia ; Mata, Manuel de la; Jaka, Oihane; Aiastui, Ana; Hernández Torres, Francisco; Aguado, Begoña ; Pérez-Alonso, Manuel; Vilchez, Jesús J.; López de Munain, Adolfo; Artero, Rubén
Issue Date2013
PublisherOxford University Press
CitationHuman Molecular Genetics 22: 704- 716 (2013)
AbstractMyotonic dystrophy type 1 (DM1) is caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Several missplicing events and transcriptional alterations have been described in DM1 patients. A large number of these defects have been reproduced in animal models expressing CTG repeats alone. Recent studies have also reported miRNA dysregulation in DM1 patients. In this work, a Drosophila model was used to investigate miRNA transcriptome alterations in the muscle, specifically triggered by CTG expansions. Twenty miRNAs were differentially expressed in CTG-expressing flies. Of these, 19 were down-regulated, whereas 1 was up-regulated. This trend was confirmed for those miRNAs conserved between Drosophila and humans (miR-1, miR-7 and miR-10) in muscle biopsies from DM1 patients. Consistently, at least seven target transcripts of these miRNAs were up-regulated in DM1 skeletal muscles. The mechanisms involved in dysregulation of miR-7 included a reduction of its primary precursor both in CTG-expressing flies and in DM1 patients. Additionally, a regulatory role for Muscleblind (Mbl) was also suggested for miR-1 and miR-7, as these miRNAs were down-regulated in flies where Mbl had been silenced. Finally, the physiological relevance of miRNA dysregulation was demonstrated for miR-10, since over-expression of this miRNA in Drosophila extended the lifespan of CTG-expressing flies. Taken together, our results contribute to our understanding of the origin and the role of miRNA alterations in DM1. © The Author 2012. Published by Oxford University Press. All rights reserved.
URIhttp://hdl.handle.net/10261/95880
DOI10.1093/hmg/dds478
Identifiersdoi: 10.1093/hmg/dds478
issn: 0964-6906
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