title: Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers.
abstract: DNA methylation and chromatin DNaseI sensitivity were analyzed in and adjacent to D4Z4 repeat arrays, which consist of 1 to approximately 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.
authors.affiliation: Human Genetics Program and Department of Biochemistry and Tulane Cancer Center, Tulane Medical School, Department of Mathematics, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsumagari
authors.forename: Lixin
authors.initials: L
authors.lastname: Qi
authors.forename: Kesmic
authors.initials: K
authors.lastname: Jackson
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Michelle
authors.initials: M
authors.lastname: Lacey
authors.forename: Janet
authors.initials: J
authors.lastname: Sowden
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Vettaikorumakankav
authors.initials: V
authors.lastname: Vedanarayanan
authors.forename: Melanie
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000737:chemistry*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry*; D003850:Deoxyribonuclease I; D044127:Epigenesis, Genetic; D054856:G-Quadruplexes; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D020080:Tandem Repeat Sequences
chemical_list: D002843:Chromatin; D004273:DNA, Neoplasm; D003850:Deoxyribonuclease I