The presence of RNA polymerase II, active or stalled, predicts epigenetic fate of promoter CpG islands
- 1 Carcinogenesis Division, National Cancer Center Research Institute, 104-0045 Tokyo, Japan;
- 2 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 104-0045 Tokyo, Japan
Abstract
Instructive mechanisms are present for induction of DNA methylation, as shown by methylation of specific CpG islands (CGIs) by specific inducers and in specific cancers. However, instructive factors involved are poorly understood, except for involvement of low transcription and trimethylation of histone H3 lysine 27 (H3K27me3). Here, we used methylated DNA immunoprecipitation (MeDIP) combined with a CGI oligonucleotide microarray analysis, and identified 5510 and 521 genes with promoter CGIs resistant and susceptible, respectively, to DNA methylation in prostate cancer cell lines. Expression analysis revealed that the susceptible genes had low transcription in a normal prostatic epithelial cell line. Chromatin immunoprecipitation with microarray hybridization (CHiP-chip) analysis of RNA polymerase II (Pol II) and histone modifications showed that, even among the genes with low transcription, the presence of Pol II was associated with marked resistance to DNA methylation (OR = 0.22; 95% CI = 0.12–0.38), and H3K27me3 was associated with increased susceptibility (OR = 11.20; 95% CI = 7.14–17.55). The same was true in normal human mammary epithelial cells for 5430 and 733 genes resistant and susceptible, respectively, to DNA methylation in breast cancer cell lines. These results showed that the presence of Pol II, active or stalled, and H3K27me3 can predict the epigenetic fate of promoter CGIs independently of transcription levels.
Footnotes
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↵3 Corresponding author.
E-mail tushijim{at}ncc.go.jp; fax 81-3-5565-1753.
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[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE15154.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.093310.109.
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- Received March 1, 2009.
- Accepted July 30, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press