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Human Molecular Genetics Advance Access published online on September 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh317
© 2004 by Oxford University Press
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Article

Genome-wide demethylation destabilizes CTG•CAG trinucleotide repeats in mammalian cells

Vera Gorbunova 1, Andrei Seluanov 1, David Mittelman 2, and John H. Wilson 2*

1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Department of Biology, University of Rochester, River Campus Box 270211, Rochester, NY 14627
2 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

* To whom correspondence should be addressed. E-mail: jwilson{at}bcm.tmc.edu.


  Abstract

Many neurological diseases, including myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias, result from intergenerational increases in the length of a CTG•CAG repeat tract. Although the basis for intergenerational repeat expansion is unclear, repeat tracts are especially unstable during germline development and production of gametes. Mammalian development is characterized by waves of genome-wide demethylation and remethylation. To test whether changes in methylation status might contribute to trinucleotide repeat instability, we examined the effects of DNA methyltransferase inhibitors on trinucleotide repeat stability in mammalian cells. Using a selectable genetic system for detection of repeat contractions in CHO cells, we showed that the rate of contractions increased more than 1000-fold upon treatment with the DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-CdR). The link between DNA demethylation and repeat instability was strengthened by similar results obtained with hydralazine treatment, which inhibits expression of DNA methyltransferase. In human cells from myotonic dystrophy patients, treatment with 5-aza-CdR strongly destabilized repeat tracts in the DMPK gene, with a clear bias toward expansion. The bias toward expansion events and changes in repeat length that occur in jumps, rather than by accumulation of small changes, are reminiscent of the intergenerational repeat instability observed in human patients. The dramatic destabilizing effect of DNA-methyltransferase inhibitors supports the hypothesis that changes in methylation patterns during epigenetic reprogramming may trigger the intergenerational repeat expansions that lead to disease.


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