title: Antisense transcription of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat.
abstract: The unstable (CTG·CAG)n trinucleotide repeat in the myotonic dystrophy type 1 (DM1) locus is bidirectionally transcribed from genes with terminal overlap. By transcription in the sense direction, the DMPK gene produces various alternatively spliced mRNAs with a (CUG)n repeat in their 3' UTR. Expression in opposite orientation reportedly yields (CAG)n-repeat containing RNA, but both structure and biologic significance of this antisense gene (DM1-AS) are largely unknown. Via a combinatorial approach of computational and experimental analyses of RNA from unaffected individuals and DM1 patients we discovered that DM1-AS spans >6 kb, contains alternative transcription start sites and uses alternative polyadenylation sites up- and downstream of the (CAG)n repeat. Moreover, its primary transcripts undergo alternative splicing, whereby the (CAG)n segment is removed as part of an intron. Thus, in patients a mixture of DM1-AS RNAs with and without expanded (CAG)n repeat are produced. DM1-AS expression appears upregulated in patients, but transcript abundance remains very low in all tissues analyzed. Our data suggest that DM1-AS transcripts belong to the class of long non-coding RNAs. These and other biologically relevant implications for how (CAG)n-expanded transcripts may contribute to DM1 pathology can now be explored experimentally.
authors.affiliation: a Radboud University Medical Center , Department of Cell Biology , Nijmegen , The Netherlands.
authors.forename: Anke E E G
authors.initials: AEEG
authors.lastname: Gudde
authors.affiliation: b Radboud University, Faculty of Science , Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences , Nijmegen , The Netherlands.
authors.forename: Simon J
authors.identifier: 0000-0002-0411-3219
authors.initials: SJ
authors.lastname: van Heeringen
authors.affiliation: a Radboud University Medical Center , Department of Cell Biology , Nijmegen , The Netherlands.
authors.forename: Amanda I
authors.identifier: 0000-0001-8315-3982
authors.initials: AI
authors.lastname: de Oude
authors.affiliation: a Radboud University Medical Center , Department of Cell Biology , Nijmegen , The Netherlands.
authors.forename: Ingeborg D G
authors.initials: IDG
authors.lastname: van Kessel
authors.affiliation: c Department of Molecular Genetics and Microbiology , Center for Neurogenetics, University of Florida College of Medicine , Gainesville , FL , USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Estabrook
authors.affiliation: c Department of Molecular Genetics and Microbiology , Center for Neurogenetics, University of Florida College of Medicine , Gainesville , FL , USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wang
authors.affiliation: a Radboud University Medical Center , Department of Cell Biology , Nijmegen , The Netherlands.
authors.forename: Bé
authors.initials: B
authors.lastname: Wieringa
authors.affiliation: a Radboud University Medical Center , Department of Cell Biology , Nijmegen , The Netherlands.
authors.forename: Derick G
authors.initials: DG
authors.lastname: Wansink
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D017398:Alternative Splicing; D016022:Case-Control Studies; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D006801:Humans; D008297:Male; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase / Q000737:chemistry / Q000235:genetics*; D016366:Open Reading Frames; D026723:Polyadenylation; D016372:RNA, Antisense / Q000737:chemistry / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics; D024363:Transcription Initiation Site; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C585517:DMPK protein, human; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D065636:Myotonin-Protein Kinase
keywords: Antisense RNA; RAN translation; bidirectional transcription; long noncoding RNA; low-abundant RNA; microsatellite instability; myotonic dystrophy; triplet repeat expansion