Postnatal development- and age-related changes in DNA-methylation patterns in the human genome

Abstract

Alterations in DNA methylation have been reported to occur during development and aging; however, much remains to be learned regarding post-natal and age-associated epigenome dynamics, and few if any investigations have compared human methylome patterns on a whole genome basis in cells from newborns and adults. The aim of this study was to reveal genomic regions with distinct structure and sequence characteristics that render them subject to dynamic post-natal developmental remodeling or age-related dysregulation of epigenome structure. DNA samples derived from peripheral blood monocytes and in vitro differentiated dendritic cells were analyzed by methylated DNA Immunoprecipitation (MeDIP) or, for selected loci, bisulfite modification, followed by next generation sequencing. Regions of interest that emerged from the analysis included tandem or interspersed-tandem gene sequence repeats (PCDHG , FAM90A , HRNR, ECEL1P2 ), and genes with strong homology to other family members elsewhere in the genome ( FZD1, FZD7 and FGF17 ). Our results raise the possibility that selected gene sequences with highly homologous copies may serve to facilitate, perhaps even provide a clock-like function for, developmental and age-related epigenome remodeling. If so, this would represent a fundamental feature of genome architecture in higher eukaryotic organisms.

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

“…Protocadherins have been shown to interact with c-Jun N-terminal kinases (JNKs) and frizzled 7 in model organisms (54). The former was the top protein -protein interaction network finding in our results, and the latter was among the top aging loci identified by Salpea et al (34). We looked for overlap with other genes identified by Bell et al (see Supplementary Material, Table S1) and genes proximal (+20 kb) to DMRs in our study.…”

“…While lacking single-base resolution, both MBD and antibodybased capture methods are capable of detecting DMRs (32) and have good genome-wide representation of the methylome (33). One previous study has used antibody-based capture and NGS to discover aging DMRs in blood DNA from a sample of 38 individuals (34).…”

Influence of environmental exposure on human epigenetic regulation

“…Similarly, puberty may constitute a period of susceptibility for alteration of the epigenome (Biro and Deardorff, 2013). Additionally, there is a body of literature examining the impact of aging on human epigenetics (Bell et al, 2012;Christensen et al, 2009;Florath et al, 2014;Garagnani et al, 2012;Hannum et al, 2013;Horvath et al, 2012;Johansson et al, 2013;Langevin et al, 2011;Madrigano et al, 2012;McClay et al, 2014;Rakyan et al, 2010;Salpea et al, 2012), which could indicate the potential importance of a lifetime of environmental exposures on epigenetic mechanisms and potentially an increased susceptibility for these alterations in an aging population.…”

Genetics and epigenetics of aging and longevity

“…Epigenetic theory of aging is a rapidly developing modern concept postulating that non-adaptive epigenetic alterations are fundamental to aging. It is well established that epimutations accumulate with age, leading to activation of genes normally downregulated epigenetically 98 , 99 . Genetically identical twins, as they age, exhibit significant differences in genome methylation pattern, leading to differences in gene expression and, ultimately, lifespan 100 , 101 .…”