Age-associated changes in DNA methylation across multiple tissues in an inbred mouse model

Helen Spiers,Eilis Hannon,Sara Wells,Brenda Williams,Cathy Fernandes,Jonathan Mill

doi:10.1016/j.mad.2016.02.001

Abstract

Epigenetic disruption has been implicated in many diseases of aging, and age-associated DNA methylation changes at specific genomic loci in humans are strongly correlated with chronological age. The aim of this study was to explore the specificity of selected age-associated differentially methylated positions (aDMPs) identified in human epidemiological studies by quantifying DNA methylation across multiple tissues in homologous regions of the murine genome. We selected four high-confidence aDMPs (located in the vicinity of the ELOVL2, GLRA1, MYOD1 and PDE4C genes) and quantified DNA methylation across these regions in four tissues (blood, lung, cerebellum and hippocampus) from male and female C57BL/6J mice, ranging in age from fetal (embryonic day 17) to 630 days. We observed tissue-specific age-associated changes in DNA methylation that was directionally consistent with those observed in humans. These findings lend further support to the notion that changes in DNA methylation are associated with chronological age and suggest that these processes are often conserved across tissues and between mammalian species. Our data highlight the relevance of utilizing model systems, in which environmental and genetic influences can be carefully controlled, for the further study of these phenomena.

Highlights

Aging, the progressive decline in physiological and psychological functioning that occurs across the lifespan, involves a complex suite of molecular changes (Lopez-Otin et al, 2013) including perturbations to the epigenetic processes regulating gene transcription (Jones et al, 2015)
We examined changes in DNA methylation with age at these four loci in three additional tissues dissected from the same individual animals
Amplicon average DNA methylation was associated with age in lung across both the ELOVL2 and GLRA1 amplicons, reflecting the patterns seen in whole blood (ELOVL2, P = 0.02; GLRA1, P = 0.01), not in cerebellum or hippocampus (Tables C.7 - C.8)

Summary

Introduction

The progressive decline in physiological and psychological functioning that occurs across the lifespan, involves a complex suite of molecular changes (Lopez-Otin et al, 2013) including perturbations to the epigenetic processes regulating gene transcription (Jones et al, 2015). Average and CpG site-specific DNA methylation across the four amplicons in each tissue is shown in Tables C.3 - C.6. Age-associated changes in DNA methylation were identified using a linear model for each of the four tissues (Table 1 and Tables C.7 - C.10).

Objectives

Results

Conclusion