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Originally published in Science Express on 4 December 2003
Science 16 January 2004:
Vol. 303. no. 5656, pp. 383 - 387
DOI: 10.1126/science.1088679
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Reports

RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy

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

Myotonic dystrophy type 1 (DM1) is caused by a CUGn 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.

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

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