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Nucleic Acids Research Advance Access originally published online on February 16, 2008
Nucleic Acids Research 2008 36(7):2196-2207; doi:10.1093/nar/gkn055
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Nucleic Acids Research, 2008, Vol. 36, No. 7 2196-2207
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers

Koji Tsumagari1, Lixin Qi1, Kesmic Jackson1, Chunbo Shao1, Michelle Lacey2, Janet Sowden3, Rabi Tawil3, Vettaikorumakankav Vedanarayanan4 and Melanie Ehrlich1,*

1Human Genetics Program and Department of Biochemistry and Tulane Cancer Center, Tulane Medical School, 2Department of Mathematics, Tulane University, New Orleans, LA 70112, 3University of Rochester Medical Center, Neuromuscular Disease Center, Rochester, NY 14642 and 4Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA

*To whom correspondence should be addressed. Tel: +1 504 988 2449; Fax: +1 504 584 1763; Email: ehrlich{at}tulane.edu

Received December 10, 2007. Revised January 9, 2008. Accepted January 28, 2008.

DNA methylation and chromatin DNaseI sensitivity were analyzed in and adjacent to D4Z4 repeat arrays, which consist of 1 to ~100 tandem 3.3-kb units at subtelomeric 4q and 10q. D4Z4 displayed hypomethylation in some cancers and hypermethylation in others relative to normal tissues. Surprisingly, in cancers with extensive D4Z4 methylation there was a barrier to hypermethylation spreading to the beginning of this disease-associated array (facioscapulohumeral muscular dystrophy, FSHD) despite sequence conservation in repeat units throughout the array. We infer a different chromatin structure at the proximal end of the array than at interior repeats, consistent with results from chromatin DNaseI sensitivity assays indicating a boundary element near the beginning of the array. The relative chromatin DNaseI sensitivity in FSHD and control myoblasts and lymphoblasts was as follows: a non-genic D4Z4-adjacent sequence (p13E-11, array-proximal)> untranscribed gene standards > D4Z4 arrays> constitutive heterochromatin (satellite 2; P < 10–4 for all comparisons). Cancers displaying D4Z4 hypermethylation also exhibited a hypermethylation-resistant subregion within the 3.3-kb D4Z4 repeat units. This subregion contains runs of G that form G-quadruplexes in vitro. Unusual DNA structures might contribute to topological constraints that link short 4q D4Z4 arrays to FSHD and make long ones phenotypically neutral.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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