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J. Biol. Chem., Vol. 280, Issue 6, 4498-4503, February 11, 2005

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Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome^*

David J. Mulvihill, Kerrie Nichol Edamura¶, Katharine A. Hagerman¶||**, Christopher E. Pearson¶||, and Yuh-Hwa Wang

From the Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, ^¶Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and ^||Department of Molecular and Medical Genetics, University of Toronto, Ontario M5G 1X8, Canada

Nucleosome packaging regulates many aspects of DNA metabolism and is thought to mediate genetic instability and transcription of expanded trinucleotide repeats. Both instability and transcription are sensitive to repeat length, tract purity, and CpG methylation. CAT or AGG interruptions within the (CAG)_n or (CGG)_n tracts of spinocerebellar ataxia, type 1 or fragile X syndrome, respectively, confer increased genetic stability to the repeats. We report the formation of nucleosomes on sequences containing pure and interrupted (CAG)_n and (CGG)_n repeats having lengths above and below the genetic stability thresholds. Increased lengths of pure repeats led to increased and decreased propensities for nucleosome assembly on the (CAG)_n and (CGG)_n repeats, respectively. CpG methylation of the CGG repeat further reduced assembly. CAT interruptions in (CAG)_n tracts decreased nucleosome assembly. In contrast, AGG interruptions in (CGG)_n tracts did not affect assembly by hypoacetylated histones. The latter observation was unaltered by CpG methylation of the repeats. However, nucleosome assembly by hyperacetylated histones on interrupted CGG tracts was increased relative to pure tracts and this effect was abolished by CpG methylation. Thus, CAT or AGG interruptions can modulate the ability of (CAG)_n and (CGG) tracts to assemble into chromatin and the effect of the AGG interruptions is dependent upon both the methylation status of the DNA and the acetylation status of the histones. Compared with the genetically unstable pure repeats, both interruptions permit a propensity of nucleosome assembly closer to that of random (genetically stable) sequences, suggesting an association of nucleosome assembly of trinucleotide repeats and genetic instability.

Received for publication, November 23, 2004 , and in revised form, December 1, 2004. , and in revised form, December 1, 2004.

^* This work was supported by grants from the Canadian Institutes of Health Research and the Fragile X Research Foundation of Canada (to C. E. P.) and from the National Institutes of Health (CA85826) (to Y.-H. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Table 1.

Both authors have contributed equally to this work.

^** Supported by National Science Engineering Research Canada.

A CHIR Scholar and a Canadian Genetic Disease Network Scholar.

To whom correspondence should be addressed: Dept. of Biochemistry, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-5050; Fax: 732-235-3232; E-mail: wangyu{at}umdnj.edu.

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