Abstract
The role of DNA methylation patterns in complex phenotypes remains unclear. To explore this question, we adapted our methods for rare variant analysis to characterize genome-wide murine DNA hybridization array to investigate methylation at CpG islands, shores, and regulatory elements. We have applied this platform to compare age and tissue- specific methylation differences in the brain and spleen of young and aged mice. As expected from prior studies, there are clear global differences in organ-specific, but not age-specific, methylation due mostly to changes at repetitive elements. Surprisingly, out of 200,000 loci there were only 946 differentially methylated cytosines (DMCs) between young and old samples (529 hypermethylated, 417 hypomethylated in aged mice) compared to thousands of tissue-specific DMCs. Hypermethylated loci were clustered around the promoter region of Sfi1, exon 2 of Slc11a2, Drg1, Esr1 and Foxa2 transcription factor binding sites. In particular, there were 75 hypermethylated Foxa2 binding sites across a 2.7 Mb region of chromosome 11. Hypomethylated loci were clustered around Mid1, Isoc2b and genome-wide loci with binding sites for Foxa2 and Esr1, which are known to play important roles in development and aging. These data suggest discreet tissue-independent methylation changes associated with aging processes such as cell division (Sfi1, Mid1), energy production (Drg1, Isoc2b) and cell death (Foxa2, Esr1).
Highlights
Aberrations in the processes that regulate healthy aging result in a wide array of disease and disability
In collaboration with Agilent, we designed a murine-specific DNA methylation hybridization array that targets up to 84 Mb of CpG islands, shores, shelves and regulatory elements in the mouse genome based on criteria described below
Using databases from the National Center for Biotechnology Information (NCBI-NIH), the University of California Santa Cruz (UCSC) Genome Browser and Ensembl (European Bioinformatics Institute/Wellcome Trust Sanger Institute; http://www.ensembl.org), we obtained the genomic coordinates for all known CpG islands, shores and shelves in the mouse genome
Summary
Aberrations in the processes that regulate healthy aging result in a wide array of disease and disability. The molecular, genetic and epigenetic regulation of these processes is only moderately understood. Epigenetic modifications (including DNA methylation) are heritable but potentially reversible and may change throughout life. Methylation of cytosine residues represents an important epigenetic mechanism that typically acts to repress gene transcription. The link between aging and DNA methylation levels has been extensively studied, and recent.
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