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Background  The exact relationship between nucleosome positioning and methylation of CpG islands in human pathogenesis is unknown.    Methodology/Principal Findings  In the present study, we characterized the nucleosome position within the  p16  CpG island and established a seeding methylation-specific PCR (sMSP) assay based on bisulfite modification to enrich the  p16  alleles containing methylated-CpG at the methylation “seeding" sites within its intron-1 in gastric carcinogenesis. The sMSP-positive rate in primary gastric carcinoma (GC) samples (36/40) was significantly higher than that observed in gastritis (19/45) or normal samples (7/13) ( P <0.01). Extensive clone sequencing of these sMSP products showed that the density of methylated-CpGs in  p16  CpG islands increased gradually along with the severity of pathological changes in gastric tissues. In gastritis lesions the methylation was frequently observed in the region corresponding to the exon-1 coding-nucleosome and the 5′UTR-nucleosome; the methylation was further extended to the region corresponding to the promoter-nucleosome in GC samples. Only few methylated-CpG sites were randomly detected within  p16  CpG islands in normal tissues. The significantly inversed relationship between the  p16  exon-1 methylation and its transcription was observed in GC samples. An exact  p16  promoter-specific 83 bp-MSP assay confirms the result of sMSP (33/55 vs. 1/6,  P <0.01). In addition,  p16  methylation in chronic gastritis lesions significantly correlated with  H. pylori  infection; however, such correlation was not observed in GC specimens.    Conclusions/Significance  It was determined that  de novo  methylation was initiated in the coding region of  p16  exon-1 in gastritis, then progressed to its 5′UTR, and ultimately to the proximal promoter in GCs. Nucleosomes may function as the basic extension/progression unit of  de novo  methylation of  p16  CpG islands  in vivo .

Nucleosomes Correlate with In Vivo Progression Pattern of De Novo Methylation of p16 CpG Islands in Human Gastric Carcinogenesis