Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans

Abstract

Environment induced epigenetic effects on gene expression in early life are likely to play important roles in mediating the risk of several immune-related diseases. In order to investigate this fully, it is essential to first document temporal changes in epigenetic profile in disease-free individuals as a prelude to defining environmentally mediated changes. Mononuclear cells (MC) were collected longitudinally from a small number of females at birth, 1 year, 2.5 years and 5 years of age and examined for changes in genome-scale DNA methylation profiles using the Illumina Infinium HumanMethylation27 BeadChip array platform. MC from two males were included for comparative purposes. Flow cytometry was used to define MC cell populations in each sample in order to exclude this as the major driver of epigenetic change. The data underwent quality control and normalization within the R programming environment. Unsupervised hierarchical clustering of samples clearly delineated neonatal MC from all other ages. A further clear distinction was observed between 1 year and 5 year samples, with 2.5 year samples showing a mixed distribution between the 1 and 5 year groups. Gene ontology of probes significantly variable over the neonatal period revealed methylation changes in genes associated with cell surface receptor and signal transduction events. In the postnatal period, methylation changes were mostly associated with the development of effector immune responses and homeostasis. Unlike all other chromosomes tested, a predominantly genetic effect was identified as controlling maintenance of X-chromosome methylation profile in females, largely refractory to change over time. This data suggests that the primary driver of neonatal epigenome is determined in utero, whilst postnatally, multiple genetic and environmental factors are implicated in the development of MC epigenetic profile, particularly between the ages of 1-5 years, when the highest level of inter individual variation is apparent. This supports a model for differential sensitivity of specific individuals to disruption in the developing epigenome during the first years of life. Further studies are now needed to examine evolving epigenetic variations in specific cell populations in relation to environmental exposures, immune phenotype and subsequent disease susceptibility.

DNA methylation and healthy human aging

“…Microarray studies confirmed a decrease in DNA methylation with age, while site‐specific analysis indicated an increase in variability of DNA methylation with age. The latter was first noted in monozygotic twins, and subsequently in unrelated individuals (Fraga et al ., 2005; Martin, 2005; Poulsen et al ., 2007; Kaminsky et al ., 2009; Martino et al ., 2011). These studies also supported the idea that DNA methylation showed reduced stringency in maintenance over the lifespan, resulting in an increase in interindividual variability along with the overall decrease in DNA methylation.…”

“…In neonatal blood, DNA methylation levels are lower than that observed at most other points during the lifespan (Martino et al ., 2011; Wang et al ., 2012). Interestingly, the age of the parents appears to affect DNA methylation in a subset of sites, perhaps relating to evidence that sperm DNA methylation is also associated with age (Adkins et al ., 2011; Jenkins et al ., 2013).…”

“…Interestingly, the age of the parents appears to affect DNA methylation in a subset of sites, perhaps relating to evidence that sperm DNA methylation is also associated with age (Adkins et al ., 2011; Jenkins et al ., 2013). After birth, average DNA methylation levels increase in blood throughout the first year of life (Martino et al ., 2011; Herbstman et al ., 2013). These changes occur preferentially at CpG island shores and shelves, enhancers, and promoters lacking CpG islands (McClay et al ., 2014).…”

“…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.…”

“…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. After the first year, median global DNA methylation levels are relatively stable, with the exception of certain regions that frequently gain DNA methylation (Martino et al ., 2011). …”