RNA leaching of transcription factors disrupts transcription in myotonic dystrophy

Science. 2004 Jan 16;303(5656):383-7. doi: 10.1126/science.1088679. Epub 2003 Dec 4.

Abstract

Myotonic dystrophy type 1 (DM1) is caused by a CUGn expansion (n approximately 50 to 5000) in the 3' untranslated region of the mRNA of the DM protein kinase gene. We show that mutant RNA binds and sequesters transcription factors (TFs), with up to 90% depletion of selected TFs from active chromatin. Diverse genes are consequently reduced in expression, including the ion transporter CIC-1, which has been implicated in myotonia. When TF specificity protein 1 (Sp1) was overexpressed in DM1-affected cells, low levels of messenger RNA for CIC-1 were restored to normal. Transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for this disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Cell Line
  • Cell Nucleus / metabolism
  • Chloride Channels / genetics
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Muscle Cells / metabolism*
  • Mutation
  • Myotonic Dystrophy / genetics*
  • Myotonin-Protein Kinase
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / genetics*
  • RNA / genetics
  • RNA / metabolism*
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, IgG / genetics
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor gamma
  • Ribonucleoproteins / metabolism
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism
  • Sp3 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*

Substances

  • CLC-1 channel
  • Chloride Channels
  • Chromatin
  • DMPK protein, human
  • DNA-Binding Proteins
  • RNA, Messenger
  • Receptors, IgG
  • Receptors, Retinoic Acid
  • Ribonucleoproteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sp1 Transcription Factor
  • Trans-Activators
  • Transcription Factors
  • Sp3 Transcription Factor
  • RNA
  • Myotonin-Protein Kinase
  • Protein Serine-Threonine Kinases