Skip Navigation


Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(23):2979-2989; doi:10.1093/hmg/ddh317
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/23/2979    most recent
ddh317v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (14)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Gorbunova, V.
Right arrow Articles by Wilson, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gorbunova, V.
Right arrow Articles by Wilson, J. H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved

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

Vera Gorbunova1,{dagger},{ddagger}, Andrei Seluanov1,{dagger},{ddagger}, David Mittelman1,2 and John H. Wilson1,2,*

1Verna and Marrs McLean Department of Biochemistry and Molecular Biology and 2Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

Received August 13, 2004; Revised September 17, 2004; Accepted September 24, 2004

Many neurological diseases, including myotonic dystrophy, Huntington's 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 >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 reprograming may trigger the intergenerational repeat expansions that lead to disease.

* To whom correspondence should be addressed at: Verna and Marrs McLean, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1 7137985760; Fax: +1 7137969438; Email: jwilson{at}bcm.tmc.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
D. Mittelman, C. Moye, J. Morton, K. Sykoudis, Y. Lin, D. Carroll, and J. H. Wilson
Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells
PNAS, June 16, 2009; 106(24): 9607 - 9612.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
V. Dion, Y. Lin, L. Hubert Jr., R. A. Waterland, and J. H. Wilson
Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline
Hum. Mol. Genet., May 1, 2008; 17(9): 1306 - 1317.
[Abstract] [Full Text] [PDF]

Home page
 J HeredHome page
J. Laidlaw, Y. Gelfand, K.-W. Ng, H. R. Garner, R. Ranganathan, G. Benson, and J. W. Fondon III
Elevated Basal Slippage Mutation Rates among the Canidae
J. Hered., August 3, 2007; (2007) esm017v2.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Napierala, A. Bacolla, and R. D. Wells
Increased Negative Superhelical Density in Vivo Enhances the Genetic Instability of Triplet Repeat Sequences
J. Biol. Chem., November 11, 2005; 280(45): 37366 - 37376.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
J. C. Chuang, C. B. Yoo, J. M. Kwan, T. W.H. Li, G. Liang, A. S. Yang, and P. A. Jones
Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2'-deoxycytidine
Mol. Cancer Ther., October 1, 2005; 4(10): 1515 - 1520.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. W. Laird
Cancer epigenetics
Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.