The criteria for a CpG-island was based on those outlined by Takai and Jones [61], where the GC ≥ 55%, Obs/Exp ≥ 0.65, and length > 300 bp which was reported to exclude most Alu-repetitive elements. We identified the genes that harbored CpG-island within a 2000 bp window upstream or downstream from the transcription start site based Human Genome Browser data base [59]. To be certain that there were no CpG island closer to the TSS and gene promoter regions, we submitted the sequences of interest (including a 2000 bp window upstream and downstream from TSS) to the CpG search engine available in reference [61] and verified that there was no CpG islands that are closer to TSS for the genes we tested. Up-regulated genes with CpG-island associations were further analyzed through the Microarray Literature-based Annotation tool MILANO [62] to look for evidence of epigenetic modifications in the literature. MILANO is a web-based tool that allows annotation of lists of genes derived from microarray results by user defined terms [62]. Using MILANO we searched for literature associations between our list of genes and the terms 'epigenetics', 'methylation' 'chromatin modification' 'cancer', and 'disease'. To identify the putative functional pathways for each gene list, we used the functional annotation enrichment tool. This tool utilizes the Gene Ontology database and uses GO Terms to identify enriched biological themes in the gene lists [63,63]. The Fisher Exact test was applied to determine the significance in the proportions of genes falling into a certain pathway in each gene list. We used this tool to look for enriched pathways of up- or down- regulated genes with CpG-island associations from the gene lists from the cell lines.