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Global, comparative analysis of tissue-specific promoter CpG methylation.

ABSTRACT: Understanding cell-type-specific epigenetic codes on a global level is a major challenge after the sequencing of the human genome has been completed. Here we applied methyl-CpG immunoprecipitation (MCIp) to obtain comparative methylation profiles of coding and noncoding genes in three human tissues, testis, brain, and monocytes. Forty-four mainly testis-specific promoters were independently validated using bisulfite sequencing or single-gene MCIp, confirming the results obtained by the MCIp microarray approach. We demonstrate the previously unknown somatic hypermethylation at many CpG-rich, testis-specific gene promoters, in particular in ampliconic areas of the Y chromosome. We also identify a number of miRNA genes showing tissue-specific methylation patterns. The comparison of the obtained tissue methylation profiles with corresponding gene expression data indicates a significant association between tissue-specific promoter methylation and gene expression, not only in CpG-rich promoters. In summary, our study highlights the exceptional epigenetic status of germ-line cells in testis and provides a global insight into tissue-specific DNA methylation patterns. Keywords: MCIp-on-Chip

ORGANISM(S): Homo sapiens

PROVIDER: GSE5548 | GEO | 2007/08/08

SECONDARY ACCESSION(S): PRJNA96041

REPOSITORIES: GEO

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Project description:<p>Aberrant DNA methylation changes are known to occur during prostate cancer progression beginning with precursor lesions. Utilizing fifty nanograms of genomic DNA in Methylplex-Next Generation Sequencing (M-NGS) we mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2). Peaks were located from mapped reads obtained in each sequencing run using a Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(<a href="http://www.sph.umich.edu/csg/qin/HPeak">http://www.sph.umich.edu/csg/qin/HPeak</a>). The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. Promoter CGI methylation gradually increased from -12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues and approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues. We observed distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome. Overall Design: We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were sequenced twice on Illumina next generation sequencing platform to access overall repeatability of M-NGS.</p>

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Global, comparative analysis of tissue-specific promoter CpG methylation.

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