Abstract
In this study we applied a new analytical strategy to investigate the relations between stochastic epigenetic mutations (SEMs) and aging. We analysed methylation levels through the Infinium HumanMethylation27 and HumanMethylation450 BeadChips in a population of 178 subjects ranging from 3 to 106 years. For each CpG probe, epimutated subjects were identified as the extreme outliers with methylation level exceeding three times interquartile ranges the first quartile (Q1-(3 x IQR)) or the third quartile (Q3+(3 x IQR)). We demonstrated that the number of SEMs was low in childhood and increased exponentially during aging. Using the HUMARA method, skewing of X chromosome inactivation (XCI) was evaluated in heterozygotes women. Multivariate analysis indicated a significant correlation between log(SEMs) and degree of XCI skewing after adjustment for age (β = 0.41; confidence interval: 0.14, 0.68; p-value = 0.0053). The PATH analysis tested the complete model containing the variables: skewing of XCI, age, log(SEMs) and overall CpG methylation. After adjusting for the number of epimutations we failed to confirm the well reported correlation between skewing of XCI and aging. This evidence might suggest that the known correlation between XCI skewing and aging could not be a direct association but mediated by the number of SEMs.
Highlights
In multicellular organisms, specificity of cell types is maintained by mitotically heritable differences in gene expression, which are in part regulated by epigenetic mechanisms
Rare or stochastic epimutations that are not shared among subjects and that minimally affect the mean methylation level of the group remain unexplored, they may play a role in phenotype development
Studies on aging well depicted common epigenetic modifications associated to the aging process, there is still a lack of knowledge regarding the rate of epigenetic mutations that stochastically arise on the genome and that are not shared among subjects
Summary
Specificity of cell types is maintained by mitotically heritable differences in gene expression, which are in part regulated by epigenetic mechanisms. These include RNA-based mechanisms, histone modifications, and DNA methylation [1]. The role of DNA methylation has been mainly explored in the context of cancer [5,6]. Findings from these studies have extensively demonstrated that www.impactaging.com
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