Age-associated hyper-methylated regions in the human brain overlap with bivalent chromatin domains

Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age-associated hyper-methylated sites in blood. In this study, we observed that age-associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00 × 10(-5)); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00 × 10(-5)). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders.