Tissue-specific dysregulation of DNA methylation in aging.
The normal aging process is a complex phenomenon associated with physiological alterations in the function of cells and organs over time. Although an attractive candidate for mediating transcriptional dysregulation, the contribution of epigenetic dysregulation to these progressive changes in cellular physiology remains unclear. In this study, we employed the genome-wide HpaII tiny fragment enrichment by ligation-mediated PCR assay to define patterns of cytosine methylation throughout the rat genome and the luminometric methylation analysis assay to measure global levels of DNA methylation in the same samples. We studied both liver and visceral adipose tissues and demonstrated significant differences in DNA methylation with age at > 5% of sites analyzed. Furthermore, we showed that epigenetic dysregulation with age is a highly tissue-dependent phenomenon. The most distinctive loci were located at intergenic sequences and conserved noncoding elements, and not at promoters nor at CG-dinucleotide-dense loci. Despite this, we found that there was a subset of genes at which cytosine methylation and gene expression changes were concordant. Finally, we demonstrated that changes in methylation occur consistently near genes that are involved in metabolism and metabolic regulation, implicating their potential role in the pathogenesis of age-related diseases. We conclude that different patterns of epigenetic dysregulation occur in each tissue over time and may cause some of the physiological changes associated with normal aging.
Thompson
Reid F
RF
Departments of Genetics, Albert Einstein College of Medicine,Bronx, NY, USA.
Atzmon
Gil
G
Gheorghe
Ciprian
C
Liang
Hong Qian
HQ
Lowes
Christina
C
Greally
John M
JM
Barzilai
Nir
N
D000375:Aging / Q000235:genetics*; D000818:Animals; D001681:Biological Assay; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D056426:Genetic Loci / Q000235:genetics; D016678:Genome / Q000235:genetics; D008163:Luminescent Measurements; D009928:Organ Specificity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D051381:Rats; D015203:Reproducibility of Results
D003596:Cytosine