Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance

Abstract

BackgroundThe extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy.ResultsIn a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change.ConclusionsOur findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program.

Distinctive topology of age-associated epigenetic drift in the human interactome

“…It is therefore plausible that gene promoters undergoing age-associated epigenetic drift should be of typically lower degree, as otherwise induced changes in gene expression at hubs could likely compromise essential cellular functions. For instance, a number of recent studies have shown that epigenetic drift is detectable even in pediatric populations (i.e., well before the reproductive period) (43,49) and that DNAm patterns in newborns are correlated with maternal age (50), suggesting that a fraction of the changes caused by epigenetic drift may be heritable. Thus, if age-associated epigenetic drift kicks in straight after birth-that is, well before the reproductive periodit is then entirely plausible that natural selection would weed out any age-associated epigenetic silencing of integral housekeeping genes, including for instance those involved in embryogenesis.…”

DNA methylation and healthy human aging

“…These changes occur preferentially at CpG island shores and shelves, enhancers, and promoters lacking CpG islands (McClay et al ., 2014). In both blood and buccal epithelial cells, DNA methylation between monozygotic twins has been shown to become more variable in the first year of life (Martino et al ., 2011, 2013). This phenomenon may indicate that the shared prenatal environment confers a high degree of epigenetic similarity between children, whereas subsequent variations in the postnatal environment result in epigenetic divergence after birth.…”

“…Further evidence for genetic contributions to epigenetic aging come from studies examining age and DNA methylation that have also observed high correlation of DNA methylation levels between twins at more than one age (Bell et al ., 2012; Martino et al ., 2013). Similar studies in adults have shown greater concordance in DNA methylation profiles between monozygotic twins than dizygotic twins (Kaminsky et al ., 2009; Bell et al ., 2011).…”

Human active X-specific DNA methylation events showing stability across time and tissues

“…16 Buccal samples used in this study were selected based on the availability of the materials and array data quality. Data from dried blood spots used in this study were from a case/control study of DNA methylation associated with preterm birth.…”