Abstract
BackgroundExtensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC). Our study aimed to characterize the genomic methylation patterns in various genomic contexts of PC. The methyl capture sequencing (methylCap-seq) method was used to map differently methylated regions (DMRs) in pooled samples from ten PC tissues and ten adjacent non-tumor (PN) tissues. A selection of DMRs was validated in an independent set of PC and PN samples using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), and methylation sensitive restriction enzyme-based qPCR (MSRE-qPCR). The mRNA and expressed sequence tag (EST) expression of the corresponding genes was investigated using RT-qPCR.ResultsA total of 1,131 PC-specific and 727 PN-specific hypermethylated DMRs were identified in association with CpG islands (CGIs), including gene-associated CGIs and orphan CGIs; 2,955 PC-specific and 2,386 PN-specific hypermethylated DMRs were associated with gene promoters, including promoters containing or lacking CGIs. Moreover, 1,744 PC-specific and 1,488 PN-specific hypermethylated DMRs were found to be associated with CGIs or CGI shores. These results suggested that aberrant hypermethylation in PC typically occurs in regions surrounding the transcription start site (TSS). The BSP, MSP, MSRE-qPCR, and RT-qPCR data indicated that the aberrant DNA methylation in PC tissue and in PC cell lines was associated with gene (or corresponding EST) expression.ConclusionsOur study characterized the genome-wide DNA methylation patterns in PC and identified DMRs that were distributed among various genomic contexts that might influence the expression of corresponding genes or transcripts to promote PC. These DMRs might serve as diagnostic biomarkers or therapeutic targets for PC.
Highlights
Extensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC)
The reads mapping to 28,691 CpG island (CGI), which were defined using the University of California, Santa Cruz (UCSC) Genome Browser, were investigated: 3.57% of the reads in the PC group and 4.25% of the reads in the pooled adjacent (PN) group were positioned at CGIs, resulting in a CGI coverage rate of 64.31% in the PC group and 64.36% in the PN group
These data indicated that our experiment provided considerable information regarding genomic CGIs (Figure 1A)
Summary
Extensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC). The methyl capture sequencing (methylCap-seq) method was used to map differently methylated regions (DMRs) in pooled samples from ten PC tissues and ten adjacent non-tumor (PN) tissues. Because most tumors that develop display particular acquired biological phenotypes, epigenetic changes must surely play important roles during tumor development [3]. At the gene particular level, genes such as p14ARF and p16INK4a [4,5] were found to display aberrant promoter methylation in PC, leading to abnormalities in gene transcription. By combining the techniques of methylated CGI amplification with Agilent 244 K Human Promoter ChIP-on-chip microarrays, the genome-wide methylation abnormalities in PC have been identified [6,7]
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