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.
Highlights
While all somatic cells in a given individual are genetically identical, different cell types form highly distinct anatomic structures and carry out a wide range of disparate physiologic functions
The most widely studied epigenetic mark is DNA cytosine methylation, most often investigated in the context of CpG island status estimate (CpGs) dinculeotides in promoter regions which often have concentrations of CpGs known as CpG islands
The known interplay of epigenetics and genetics, makes it clear that a more complete characterization of epigenetic variation and its sources must be accomplished to reach the goal of a complete understanding of disease
Summary
While all somatic cells in a given individual are genetically identical (excepting T and B cells), different cell types form highly distinct anatomic structures and carry out a wide range of disparate physiologic functions. The vast repertoire of cellular phenotypes is made possible largely via epigenetic control of gene expression, which is known to play a critical role in cellular differentiation. Epigenetics is the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence [1], and includes critical normal processes such as X-chromosome inactivation and genomic imprinting. The most widely studied epigenetic mark is DNA cytosine methylation, most often investigated in the context of CpG dinculeotides in promoter regions which often have concentrations of CpGs known as CpG islands. Just as normal genetic variation is understood to be associated with a predisposition to a vast array of human
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