Abstract
BackgroundEarly life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies.MethodsTo this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects.ResultsWe found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements.ConclusionsThese data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.
Highlights
Life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence
Genome‐wide profiling of DNA methylation changes during the first years of life To characterize DNA methylation changes that occur during the first years of life, we analyzed the methylation status of 783,659 CpG sites in cord, 5-year-old and 10-year-old paired blood samples from subjects using the Illumina Infinium MethylationEPIC BeadChip
As compared to the distribution of the array background, hypermethylated CpGs were found to be enriched at CpG islands for both 0 → 5 and 5 → 10 changes (Fisher’s test; both p < 0.001, odds ratios (ORs) = 1.2 and 7.4, respectively) and impoverished at open sea locations (Fisher’s test; both p < 0.001, ORs = 0.6 and 0.2 respectively), while the inverse was the case for hypomethylated CpGs, that is they were very enriched at open sea regions (Fisher’s test; both p < 0.001, ORs = 2.4 and 6.9, for 0 → 5 and 5 → 10, respectively) and very impoverished at CpG islands (Fisher’s test; both p < 0.001, ORs = 0.1 and 0.03 for 0 → 5 and 5 → 10, respectively)
Summary
Life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. The epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies Epigenetic modifications such as DNA methylation are known to influence gene expression and biological function [1] and alterations in epigenetic marks are found in processes ranging from physiological development and cellular differentiation [2] to pathological scenarios, as well as aging [3, 4]. Epigenetic modification continues to take place throughout the human lifespan, both at the DNA methylation and chromatin levels [6] and precise DNA methylation markers of age have recently been developed [7] It seems, that the first years of life constitute the post-natal period with the most substantial epigenetic changes [8, 9] and, prenatal and early life epigenetic aggression has been linked to countless health-related consequences in a wide variety of settings [10]. Longitudinal DNA methylation studies which analyze data from more than two time points remain scarce [17,18,19] and most of the previous literature stands on surpassed methylation screening technologies such as the Infinium Human Methylation 450K BeadChip which mainly interrogates CpG-dense genomic regions, even though the functional association between DNA methylation and gene expression is increasingly being described for CpG-sparse locations such as enhancers and gene bodies [20]
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