title: Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy.
abstract: Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rau
authors.forename: Fernande
authors.initials: F
authors.lastname: Freyermuth
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fugier
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Villemin
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Fischer
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembele
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
authors.forename: Annie
authors.initials: A
authors.lastname: Nicole
authors.forename: Denis
authors.initials: D
authors.lastname: Duboc
authors.forename: Karim
authors.initials: K
authors.lastname: Wahbi
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.forename: Natacha
authors.initials: N
authors.lastname: Dreumont
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
mesh_terms: D001667:Binding, Competitive; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D008957:Models, Genetic; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D043244:Ribonuclease III / Q000502:physiology; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C000715187:Lin28A protein, human; C493663:MBNL1 protein, human; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C511130:TUT4 protein, human; D043244:Ribonuclease III