Using MIRA-seq, we have characterized the DNA methylome of metastatic melanoma 
and normal melanocytes. Individual tumors contained several thousand 
hypermethylated regions. We discovered 179 tumor-specific methylation peaks 
present in all (27/27) melanomas that may be effective disease biomarkers, and 
3113 methylation peaks were seen in >40% of the tumors. We found that 150 of the 
approximately 1200 tumor-associated methylation peaks near transcription start 
sites (TSSs) were marked by H3K27me3 in melanocytes. DNA methylation in melanoma 
was specific for distinct H3K27me3 peaks rather than for broadly covered 
regions. However, numerous H3K27me3 peak-associated TSS regions remained devoid 
of DNA methylation in tumors. There was no relationship between BRAF mutations 
and the number of methylation peaks. Gene expression analysis showed upregulated 
immune response genes in melanomas presumably as a result of lymphocyte 
infiltration. Down-regulated genes were enriched for melanocyte differentiation 
factors; e.g., KIT, PAX3 and SOX10 became methylated and downregulated in 
melanoma.