DNA methylation determines nucleosome occupancy in the 5′-CpG islands of tumor suppressor genes

• Published in: Oncogene Vol. 32; no. 47; pp. 5421 - 5428
• Main Authors: Portela, A, Liz, J, Nogales, V, Setién, F, Villanueva, A, Esteller, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-11-2013; Nature Publishing Group
• Subjects: 631/208/176/1988; 631/45/612/100/1701; 631/67/581; Apoptosis; Cancer; Cell Biology; Cell Line, Tumor; Chromatin Assembly and Disassembly; CpG Islands - genetics; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - deficiency; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA methylation; DNA Methylation - genetics; DNA Methyltransferase 3B; DNA sequencing; Epigenetics; Gene expression; Genes, Tumor Suppressor; Genetic aspects; HCT116 Cells; Human Genetics; Humans; Identification and classification; Internal Medicine; Medicine; Medicine & Public Health; Methylation; Nucleosomes; Nucleosomes - genetics; Nucleosomes - metabolism; Nucleotide sequencing; Oncology; Original; original-article; Promoter Regions, Genetic - genetics; Tumor suppressor genes; DNA methylation; nucleosome; DNA methyltransferase; CpG island; tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.162

Promoter CpG island hypermethylation of tumor suppressor genes is an epigenetic hallmark of human cancer commonly associated with nucleosome occupancy and the transcriptional silencing of the neighboring gene. Nucleosomes can determine the underlying DNA methylation status. Herein, we show that the opposite is also true: DNA methylation can determine nucleosome positioning. Using a cancer model and digital nucleosome positioning techniques, we demonstrate that the induction of DNA hypomethylation events by genetic (DNMT1/DNMT3B deficient cells) or drug (a DNA demethylating agent) approaches is associated with the eviction of nucleosomes from previously hypermethylated CpG islands of tumor suppressor genes. Most importantly, the establishment of a stable cell line that restores DNMT1/DNMT3B deficiency shows that nucleosomes reoccupy their positions in
de novo
methylated CpG islands. Finally, we extend these results to the genomic level, combining a DNA methylation microarray and the nucleosome positioning technique. Using this global approach, we observe the dependency of nucleosome occupancy upon the DNA methylation status. Thus, our results suggest that there is a close association between hypermethylated CpG islands and the presence of nucleosomes, such that each of these epigenetic mechanisms can determine the recruitment of the other.