Abstract
BackgroundAge-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip.ResultsAfter filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm.ConclusionsThis study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0064-6) contains supplementary material, which is available to authorized users.
Highlights
Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation
The present study provides a catalogue of 794 age-modified CpG sites that robustly reflect the changes in DNA methylation levels that occur in human blood leukocytes within 3 to 60 months after birth
We analysed the longitudinal changes in DNA methylation in a total of 60 samples at 3, 6, 12, 24, 36, 48 and 60 months after birth, using serial DNA samples extracted from peripheral blood leukocytes of ten healthy girls participating in the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) (Table 1)
Summary
Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. Other DNA methylation patterns are very dynamic, change during lifetime and mediate several physiological events such as cell differentiation, cell maturation and tissue-specific gene expression [1,2]. Studies in diverse human tissues have demonstrated that DNA methylation levels are modified as a function of age [6,7,8,9,10]. Most studies investigating age-associated DNA methylation changes have been performed in adults and from the perspective of cell senescence, longevity, cancer, stem cell functions and chronological age [12,14,15,16,17,18,19]. Few studies have documented the dynamics of DNA methylation during early childhood [20,21,22,23]
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