Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy

Nat Struct Mol Biol. 2011 Jun 19;18(7):840-5. doi: 10.1038/nsmb.2067.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology
  • Humans
  • MicroRNAs / chemistry
  • MicroRNAs / metabolism*
  • Models, Genetic
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / metabolism
  • Nucleic Acid Conformation
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Ribonuclease III / physiology
  • Trinucleotide Repeat Expansion
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Lin28A protein, human
  • MBNL1 protein, human
  • MIRN1 microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • TUT4 protein, human
  • Ribonuclease III