RNA leaching of transcription factors disrupts transcription in myotonic dystrophy.
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.
Ebralidze
A
A
Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School and Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Boston, MA 02215, USA.
Wang
Y
Y
Petkova
V
V
Ebralidse
K
K
Junghans
R P
RP
D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D032342:Muscle Cells / Q000378:metabolism*; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051705:Sp3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000097768:Retinoic Acid Receptor gamma
D018118:Chloride Channels; D002843:Chromatin; D004268:DNA-Binding Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D012333:RNA, Messenger; D017452:Receptors, IgG; D018168:Receptors, Retinoic Acid; D012261:Ribonucleoproteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C086321:CLC-1 channel; C585517:DMPK protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human