Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets

Ordway, J. M., Bedell, J. A., Citek, R. W., Nunberg, A., Garrido, A., Kendall, R., Stevens, J. R., Cao, D., Doerge, R. W., Korshunova, Y., Holemon, H., McPherson, J. D., Lakey, N., Leon, J., Martienssen, R. A., Jeddeloh, J. A. (2006) Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis, 27 (12). pp. 2409-23. ISSN 0143-3334 (Print)0143-3334 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/16952911
DOI: 10.1093/carcin/bgl161

Abstract

Using a unique microarray platform for cytosine methylation profiling, the DNA methylation landscape of the human genome was monitored at more than 21,000 sites, including 79% of the annotated transcriptional start sites (TSS). Analysis of an oligodendroglioma derived cell line LN-18 revealed more than 4000 methylated TSS. The gene-centric analysis indicated a complex pattern of DNA methylation exists along each autosome, with a trend of increasing density approaching the telomeres. Remarkably, 2% of CpG islands (CGI) were densely methylated, and 17% had significant levels of 5 mC, whether or not they corresponded to a TSS. Substantial independent verification, obtained from 95 loci, suggested that this approach is capable of large scale detection of cytosine methylation with an accuracy approaching 90%. In addition, we detected large genomic domains that are also susceptible to DNA methylation reinforced inactivation, such as the HOX cluster on chromosome 7 (CH7). Extrapolation from the data suggests that more than 2000 genomic loci may be susceptible to methylation and associated inactivation, and most have yet to be identified. Finally, we report six new targets of epigenetic inactivation (IRX3, WNT10A, WNT6, RARalpha, BMP7 and ZGPAT). These targets displayed cell line and tumor specific differential methylation when compared with normal brain samples, suggesting they may have utility as biomarkers. Uniquely, hypermethylation of the CGI within an IRX3 exon was correlated with over-expression of IRX3 in tumor tissues and cell lines relative to normal brain samples.

Item Type: Paper
Uncontrolled Keywords: Brain physiology physiopathology Brain Neoplasms genetics Cell Line Tumor DNA Methylation Gene Expression Profiling Genome Human Humans Neoplasm Proteins genetics Oligodendroglioma genetics Polymerase Chain Reaction Reference Values Transcription Genetic
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
organism description > animal > mammal > primates > hominids > human
CSHL Authors:
Communities: CSHL labs > Martienssen lab
Depositing User: Matt Covey
Date Deposited: 01 Mar 2013 17:21
Last Modified: 01 Mar 2013 17:21
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27656

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