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

By Brock C. Christensen, Eugene Andres Houseman, Carmen J. Marsit, S. Zheng, M. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas, James F. Padbury, R. Bueno and 4 more. PLoS Genetics, 2009

1,102 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d888e90019d4a9beff027f9621546551c08270ae

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Citations in the corpus

Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population (2012, result): “We found an enrichment of a-DMRs in CpG islands (see Figure 4A), which is consistent with previous observations for hyper-methylated a-DMRs [14,28].”
Epigenome-Wide Association Studies for common human diseases (2011, background): “Third, it could be environmentally induced, either by adult lifestyle-related factors, such as diet or smokin”
Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome (2011, background): “Among these, the 1,505 CpG (Illumina GoldenGate DNA Methylation BeadArray),(20-23) and 27,000 CpG (Illumina Infinium HumanMethylation27 BeadChip),(24-27) microarrays have proved to be useful for addressing various biological and medical questions in a range of independent studies in areas such as ca”
Aging effects on DNA methylation modules in human brain and blood tissue (2012, background): “13 Validation 50 CD14+CD4+ CD4+ T-cells and CD14+ monocytes 36 16-69 Infin 27 k [14] GSE20242”
An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease (2016, background): “Measures incorporating DNA methylation levels have recently given rise to a new class of biomarkers that appear informative of aging given that age has a profound effect on DNA methylation levels in most human tissues and cell types [10–18].”
DNA methylation age of blood predicts all-cause mortality in later life (2015, neutral): “Unlike genomic variants, such as single nucleotide polymorphisms (SNPs), levels of DNA methylation vary across the life course [2-6].”
Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates (2012, positive): “In particular, DNA methylation associates with chronological age over long time scales (Alisch et al., 2012; Christensen et al., 2009; Bollati et al., 2009; Boks et al., 2009; Rakyan et al., 2010; Bocklandt et al., 2011; Bell et al., 2012), and changes in methylation have been linked to complex…”
Epigenetic clock analysis of diet, exercise, education, and lifestyle factors (2017, neutral): “Chronological age has been shown to have a profound effect on DNA methylation levels [26-34].”