A Multifactorial Signature of DNA Sequence and Polycomb Binding Predicts Aberrant CpG Island Methylation

• Authors: Michael T. McCabe, Emory University; Eva K. Lee, Emory University; Paula M Vertino, Emory University
• Journal Title: Cancer Research
• Volume: Volume 69, Number 1
• Publisher: American Association for Cancer Research | 2009-01-01, Pages 282-291
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-08-3274
• Subjects: Health Sciences, Oncology; Biology, Genetics
• Keywords: DNA methylation; supervised learning; DNMT1; PRC2; polycomb; H3K27me3

Abstract

Aberrant CpG island methylation is associated with transcriptional silencing of regulatory genes in human cancer. While most CpG islands remain unmethylated, a subset accrues aberrant methylation in cancer via unknown mechanisms. Previously, we showed that CpG islands differ in their intrinsic propensity towards hypermethylation. We developed a classifier (PatMAn) based on the frequencies of seven DNA sequence patterns that discriminated methylation-prone (MP) and methylation-resistant (MR) CpG islands. Here we report on the genome-wide application and direct testing of PatMAn in cancer. Although trained on data from a cell culture model of de novo methylation involving overexpression of DNMT1, PatMAn accurately predicted CpG islands at increased risk of hypermethylation in cancer cell lines and primary tumors. Analysis of CpG islands predicted to be MP revealed a strong association with embryonic targets of Polycomb Repressive Complex 2 (PRC2), indicating that PatMAn predicts not only aberrant methylation, but also PRC2 binding. A second classifier (SUPER-PatMAn) that integrates the seven PatMAn DNA patterns with SUZ12 protein enriched regions as a marker of PRC2 occupancy showed improved performance (prediction accuracy=81-88%). In addition to many non-PRC2 targets, SUPER-PatMAn identified a subset of PRC2 targets that were more likely to be hypermethylated in cancer. Genome-wide, CpG islands predicted to be MP were enriched in genes known to undergo hypermethylation in cancer, genes functioning in transcriptional regulation, and components of developmental pathways. These findings demonstrate that hypermethylation of certain gene loci is controlled in part by an underlying susceptibility influenced by both local sequence context and trans-acting factors.