Factors underlying variable DNA methylation in a human community cohort

Abstract

Epigenetics is emerging as an attractive mechanism to explain the persistent genomic embedding of early-life experiences. Tightly linked to chromatin, which packages DNA into chromosomes, epigenetic marks primarily serve to regulate the activity of genes. DNA methylation is the most accessible and characterized component of the many chromatin marks that constitute the epigenome, making it an ideal target for epigenetic studies in human populations. Here, using peripheral blood mononuclear cells collected from a community-based cohort stratified for early-life socioeconomic status, we measured DNA methylation in the promoter regions of more than 14,000 human genes. Using this approach, we broadly assessed and characterized epigenetic variation, identified some of the factors that sculpt the epigenome, and determined its functional relation to gene expression. We found that the leukocyte composition of peripheral blood covaried with patterns of DNA methylation at many sites, as did demographic factors, such as sex, age, and ethnicity. Furthermore, psychosocial factors, such as perceived stress, and cortisol output were associated with DNA methylation, as was early-life socioeconomic status. Interestingly, we determined that DNA methylation was strongly correlated to the ex vivo inflammatory response of peripheral blood mononuclear cells to stimulation with microbial products that engage Toll-like receptors. In contrast, our work found limited effects of DNA methylation marks on the expression of associated genes across individuals, suggesting a more complex relationship than anticipated.population cohort | early-life environment | immune response

Plasticity of DNA methylation in a nerve injury model of pain

“…22 An increasing number of reports have further proposed that the methylome-transcriptome relationship cannot be represented by a simple model when considering large, high quality datasets. 10,21,23,36,37 In these studies, positive and negative correlations between methylation alterations and transcriptome changes were found only for a minority of CpGs. It was also suggested that the relationship depends on the CpG-content of the promoter region.…”

DNA methylation and healthy human aging

“…Smoking‐associated DNA methylation changes have also been found in genes involved in inflammatory networks, important candidates in the risk of age‐related diseases such as heart disease and stroke (Breitling et al ., 2012; Dogan et al ., 2014). Other environmental influences, such as abuse or adversities in childhood, have also been linked to stable DNA methylation differences that persist into adulthood (Meaney, 2010; Essex et al ., 2011; Borghol et al ., 2012; Lam et al ., 2012; Klengel et al ., 2013). The accumulation of these environmental exposures, either shared or unshared across individuals, would then contribute to epigenetic change with age.…”

“…It is important to note that many of the studies discussed in this review have not been adjusted for differences in cellular composition with age. Therefore, tissue‐specific epigenetic clock sites in some of these studies may not be accurate; however, the overall patterns of DNA methylation change with age have been validated in studies that did correct for cellular composition (Lam et al ., 2012; Lister et al ., 2013; Jaffe & Irizarry, 2014). …”

“…Approximately 60–70% of genes have a CpG island associated with their promoters, and promoters can be classified according to their CpG density (Saxonov et al ., 2006; Weber et al ., 2007). Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al ., 2007; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014).…”

“…Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al ., 2007; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al ., 2009; Gutierrez Arcelus et al ., 2013).…”