title: Expanded CTG repeats trigger miRNA alterations in Drosophila that are conserved in myotonic dystrophy type 1 patients.
abstract: Myotonic 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.
authors.affiliation: Department of Genetics, University of Valencia, Burjasot 46100, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Fernandez-Costa
authors.forename: Amparo
authors.initials: A
authors.lastname: Garcia-Lopez
authors.forename: Sheila
authors.initials: S
authors.lastname: Zuñiga
authors.forename: Victoria
authors.initials: V
authors.lastname: Fernandez-Pedrosa
authors.forename: Amelia
authors.initials: A
authors.lastname: Felipo-Benavent
authors.forename: Manuel
authors.initials: M
authors.lastname: Mata
authors.forename: Oihane
authors.initials: O
authors.lastname: Jaka
authors.forename: Ana
authors.initials: A
authors.lastname: Aiastui
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernandez-Torres
authors.forename: Begoña
authors.initials: B
authors.lastname: Aguado
authors.forename: Manuel
authors.initials: M
authors.lastname: Perez-Alonso
authors.forename: Jesus J
authors.initials: JJ
authors.lastname: Vilchez
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Artero
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008017:Life Expectancy; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome; D019680:Trinucleotide Repeat Expansion
chemical_list: D029721:Drosophila Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C109271:mbl protein, Drosophila