RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy

Myotonic dystrophy type 1 (DM1) is caused by a$CUG_n$expansion ($n \approx 50 to 5000$) 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 chromat...

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Veröffentlicht in:Science (American Association for the Advancement of Science) 2004-01, Vol.303 (5656), p.383-387
Hauptverfasser: Ebralidze, A., Wang, Y., Petkova, V., Ebralidse, K., Junghans, R. P.
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Sprache:eng
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Zusammenfassung:Myotonic dystrophy type 1 (DM1) is caused by a$CUG_n$expansion ($n \approx 50 to 5000$) 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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1088679