Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context

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Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context

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dc.contributor.author Christensen, Brock C.
dc.contributor.author Marsit, Carmen J.
dc.contributor.author Zheng, Shichun
dc.contributor.author Wrensch, Margaret R.
dc.contributor.author Wiemels, Joseph L.
dc.contributor.author Nelson, Heather H.
dc.contributor.author Karagas, Margaret R.
dc.contributor.author Padbury, James F.
dc.contributor.author Yeh, Ru-Fang
dc.contributor.author Wiencke, John K.
dc.contributor.author Kelsey, Karl T.
dc.contributor.author Houseman, Eugene Andres
dc.contributor.author Bueno, Raphael
dc.contributor.author Sugarbaker, David John
dc.date.accessioned 2011-05-09T04:08:57Z
dc.date.issued 2009
dc.identifier.citation Christensen, Brock C., E. Andres Houseman, Carmen J. Marsit, Shichun Zheng, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, et al. 2009. Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context. PLoS Genetics 5(8): e1000602. en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4882990
dc.description.abstract Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island–dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pgen.1000602 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718614/pdf/ en_US
dash.license LAA
dc.subject developmental biology en_US
dc.subject aging en_US
dc.subject genetics and genomics en_US
dc.subject bioinformatics en_US
dc.subject epigenetics en_US
dc.subject population genetics en_US
dc.subject molecular biology en_US
dc.subject DNA methylation en_US
dc.subject public health and epidemiology en_US
dc.subject environmental health en_US
dc.title Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author Houseman, Eugene Andres
dc.date.available 2011-05-09T04:08:57Z
dash.affiliation.other SPH^Biostatistics en_US
dash.affiliation.other HMS^Surgery-Brigham and Women's Hospital en_US

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