title: The influence of cis-regulatory elements on DNA methylation fidelity.
abstract: It is now established that, as compared to normal cells, the cancer cell genome has an overall inverse distribution of DNA methylation ("methylome"), i.e., predominant hypomethylation and localized hypermethylation, within "CpG islands" (CGIs). Moreover, although cancer cells have reduced methylation "fidelity" and genomic instability, accurate maintenance of aberrant methylomes that underlie malignant phenotypes remains necessary. However, the mechanism(s) of cancer methylome maintenance remains largely unknown. Here, we assessed CGI methylation patterns propagated over 1, 3, and 5 divisions of A2780 ovarian cancer cells, concurrent with exposure to the DNA cross-linking chemotherapeutic cisplatin, and observed cell generation-successive increases in total hyper- and hypo-methylated CGIs. Empirical bayesian modeling revealed five distinct modes of methylation propagation: (1) heritable (i.e., unchanged) high-methylation (1186 probe loci in CGI microarray); (2) heritable (i.e., unchanged) low-methylation (286 loci); (3) stochastic hypermethylation (i.e., progressively increased, 243 loci); (4) stochastic hypomethylation (i.e., progressively decreased, 247 loci); and (5) considerable "random" methylation (582 loci). These results support a "stochastic model" of DNA methylation equilibrium deriving from the efficiency of two distinct processes, methylation maintenance and de novo methylation. A role for cis-regulatory elements in methylation fidelity was also demonstrated by highly significant (p<2.2×10(-5)) enrichment of transcription factor binding sites in CGI probe loci showing heritably high (118 elements) and low (47 elements) methylation, and also in loci demonstrating stochastic hyper-(30 elements) and hypo-(31 elements) methylation. Notably, loci having "random" methylation heritability displayed nearly no enrichment. These results demonstrate an influence of cis-regulatory elements on the nonrandom propagation of both strictly heritable and stochastically heritable CGIs.
authors.affiliation: Harbin Institute of Technology, School of Computer Science and Technology, Harbin, Heilongjiang, China.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Teng
authors.forename: Curt
authors.initials: C
authors.lastname: Balch
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Lang
authors.initials: L
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014157:Transcription Factors; D002945:Cisplatin