A method of sample-wise region-set enrichment analysis for DNA methylomics.

Gene set analysis has commonly been used to interpret DNA methylome data. However, summarizing the DNA methylation level of a gene is challenging due to variability in the number, density and methylation levels of CpG sites, and the numerous intergenic CpGs. Instead, we propose to use region sets to annotate the DNA methylome. We developed single sample region-set enrichment analysis for DNA methylome (methyl-ssRSEA) to conduct sample-wise, region-set enrichment analysis. Methyl-ssRSEA can handle both microarray- and sequencing-based platforms and reproducibly recover the known biology from the methylation profiles of peripheral blood cells and breast cancers. The performance was superior to existing tools for region-set analysis in discriminating blood cell types. Methyl-ssRSEA offers a novel way to functionally interpret the DNA methylome in the cell.