Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation

Promoter region CpG island methylation is associated with tumor suppressor gene silencing in neoplasia. GenBank sequence analyses revealed that a number of CpG islands are juxtaposed to multiple Alu repeats, which have been proposed as "de novo methylation centers." These islands also cont...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-08, Vol.272 (35), p.22322-22329
Main Authors: Graff, J R, Herman, J G, Myöhänen, S, Baylin, S B, Vertino, P M
Format: Article
Language:English
Subjects:
Base Sequence
Breast - chemistry
Cadherins - genetics
Chromosome Mapping
CpG Islands
DNA Methylation
DNA, Neoplasm - metabolism
DNA-Cytosine Methylases - metabolism
Female
Genes, Tumor Suppressor
Humans
Molecular Sequence Data
Tumor Cells, Cultured
von Hippel-Lindau Disease - genetics
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Summary:Promoter region CpG island methylation is associated with tumor suppressor gene silencing in neoplasia. GenBank sequence analyses revealed that a number of CpG islands are juxtaposed to multiple Alu repeats, which have been proposed as "de novo methylation centers." These islands also contain multiple Sp1 elements located upstream and downstream of transcription start, which have been shown to protect CpG islands from methylation. We mapped the methylation patterns of the E-cadherin (E-cad) and von Hippel-Lindau (VHL) tumor suppressor gene CpG island regions in normal and neoplastic cells. Although unmethylated in normal tissue, these islands were embedded between densely methylated flanking regions containing multiple Alu repeats. These methylated flanks were segregated from the unmethylated, island CpG sites by Sp1-rich boundary regions. Finally, in human fibroblasts overexpressing DNA methyltransferase, de novo methylation of the E-cad CpG island initially involved sequences at both ends of the island and the adjacent, flanking regions and progressed with time to encompass the entire CpG island region. Together, these data suggest that boundaries exist at both ends of a CpG island to maintain the unmethylated state in normal tissue and that these boundaries may be progressively overridden, eliciting the de novo methylation associated with tumor suppressor gene silencing in neoplasia.
ISSN:0021-9258
DOI:10.1074/jbc.272.35.22322