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

TLDR

Epigenetic regulation of gene transcription is essential for development and differentiation, yet normal tissue variation in DNA methylation driven by age or environmental exposures remains poorly understood. The study aims to characterize how aging and environmental factors shape normal tissue‑specific DNA methylation patterns. The authors profiled 1,413 autosomal CpG sites across 217 healthy tissues from ten anatomical sites to assess tissue‑specific methylation and its association with age and exposures. They identified distinct methylation classes that predict tissue type and age, with CpG island‑dependent age effects—methylation increases in islands and decreases outside islands—highlighting age‑ and exposure‑driven epigenetic changes relevant to disease risk.

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.