Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers.
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.
Tsumagari
Koji
K
Human Genetics Program and Department of Biochemistry and Tulane Cancer Center, Tulane Medical School, Department of Mathematics, Tulane University, New Orleans, LA 70112, USA.
Qi
Lixin
L
Jackson
Kesmic
K
Shao
Chunbo
C
Lacey
Michelle
M
Sowden
Janet
J
Tawil
Rabi
R
Vedanarayanan
Vettaikorumakankav
V
Ehrlich
Melanie
M
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
D002843:Chromatin; D004273:DNA, Neoplasm; D003850:Deoxyribonuclease I