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Parallel analysis of the epigenome: DNA methylation and histone modifications
Alice N.C. Kuo, (akuo@bccrc.ca); Jonathan J. Davies, Ian M. Wilson, Raj Chari, Wan L. Lam; Cancer Genetics, British Columbia Cancer Research Centre and Pathology and Laboratory Medicine, University of British Columbia, Canada
Content: Epigenomics is the study of heritable yet reversible modifications to the genome. The most studied events such as DNA methylation and histone modifications have been correlated to tumourigenesis. Histones compact double stranded DNA into nucleosomes and further into chromatin. Depending on modifications to the histones, chromatin can exist in two different states, namely euchromatin (transcriptionally active) and heterochromatin (transcriptionally inactive). Although we know the mechanisms of DNA methylation and histone modification, we know little about the contributions from each event in tumourigenesis. This study uses an integrative approach to perform parallel analysis of DNA methylation and histone H3K9 modification at a global level.
Technology: The experimental platform technology couples an immunocapture method for isolating methylated DNA or DNA/histone complexes with DNA microarray technology. The whole genome tiling path arrays used are imaged using a ScanArray HT Microarray scanner. Images are analyzed and spot ratio values calculated using SoftWorxâ. The bioinformatics platform technologies used are SeeGH visualization software and System for Integrative Genomic Microarray Analysis (SIGMA) viewer.
Design: For this epigenetic study, chromatin immunoprecipitation (ChIP) on microarray chip technique is performed. Antibodies specific to methylated DNA or H3K9 modifications including acetylation, monomethylation, dimethylation, and trimethylation are used to immunoprecipitate methylated DNA or DNA/histone complexes. Immunocaptured DNA is labeled and hybridized to the whole genome tiling path array. DNA methylation and histone H3K9 modification array data are mapped to genome location using SIGMA viewer and multiple data sets are integratively analyzed. Residual log2 profiles are generated to reveal differential regions of DNA methylation and H3K9 modifications. By aligning the profiles, we identify regions that may correlate to inactive transcription in the cancer genome.
Results and Conclusion: Regions of differential DNA methylation and histone H3K9 modification were identified. Additionally, in regions enriched for H3K9 acetylation, we see a depletion in mono-, di- and tri- methylation as expected. Our data shows an integrated description of the epigenome at a high resolution in a parallel manner.
