TY - JOUR
T1 - The influence of cis-regulatory elements on DNA methylation fidelity
AU - Teng, Mingxiang
AU - Balch, Curt
AU - Liu, Yunlong
AU - Li, Meng
AU - Huang, Tim H.M.
AU - Wang, Yadong
AU - Nephew, Kenneth P.
AU - Li, Lang
N1 - Funding Information:
The authors wish to thank Dr. Fang Fang (Medical Sciences, Indiana University), Thomas Chen (a summer fellow of the National Cancer Institute's Integrative Cancer Biology Program) for computational assistance, and Dave Miller, for valuable discussions. The gene expression microarray studies were carried out using the facilities of the Center for Medical Genomics at Indiana University School of Medicine. The Center for Medical Genomics is supported in part by the Indiana Genomics Initiative of Indiana University, INGEN, which is supported in part by the Lilly Endowment, Inc.
PY - 2012/3/6
Y1 - 2012/3/6
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0032928
DO - 10.1371/journal.pone.0032928
M3 - Article
C2 - 22412954
AN - SCOPUS:84863248732
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 3
M1 - e32928
ER -