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Published Online December 4, 2003
Science DOI: 10.1126/science.1088679

Reports

Submitted on July 2, 2003
Accepted on November 19, 2003

RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy

A. Ebralidze 1, Y. Wang 1, V. Petkova 1, K. Ebralidse 1, R. P. Junghans 1*

1 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.

* To whom correspondence should be addressed. E-mail: junghans{at}hms.harvard.edu.

Myotonic dystrophy type 1 is caused by a CUGn expansion (n {approx}50-5000) 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 a near 90% depletion of selected TFs from active chromatin. Diverse genes are consequently reduced in expression, including the ion-transporter, CIC-1, that has been implicated in myotonia. When TF Specificity protein 1 (Sp1) was overexpressed in DM1-affected cells, low levels of mRNA for CIC-1 were restored to normal. Transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for this disease.


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