Analysis of the Machinery and Intermediates of the 5hmC-mediated DNA Demethylation Pathway in Aging on Samples From the MARK-AGE Study

Aging (Albany NY). 2016 Aug 29;8(9):1896-1922. doi: 10.18632/aging.101022.

Abstract

Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project 'MARK-AGE'. The results provide evidence for an age-related decline of TET1, TET3 and TDG gene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly.

Keywords: DNA hydroxymethylation; TDG; aging; genesTET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism*
  • Adult
  • Aged
  • Aging / genetics*
  • Aging / metabolism
  • DNA Methylation*
  • Dioxygenases / genetics*
  • Dioxygenases / metabolism
  • Female
  • Gene Expression
  • Gene Expression Regulation*
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Mixed Function Oxygenases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism

Substances

  • Proto-Oncogene Proteins
  • 5-Methylcytosine
  • Mixed Function Oxygenases
  • TET1 protein, human
  • TET3 protein, human
  • Dioxygenases