Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARKAGE Study

Elisabetta Valentini, Michele Zampieri, Marco Malavolta, Maria Giulia Bacalini, Roberta Calabrese, Tiziana Guastafierro, Anna Reale, Claudio Franceschi, Antti Hervonen, Bernhard Koller, Jürgen Bernhardt, Peternella Eline Slagboom, Olivier Toussaint, Ewa Sikora, Efstathios S. Gonos, Nicolle Breusing, Tilman Grune, Eugène Jansen, Martijn E T Dollé, Maria Moreno-VillanuevaThilo Sindlinger, Alexander Bürkle, Fabio Ciccarone, Paola Caiafa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1896-1922
Number of pages27
JournalAging
Volume8
Issue number9
DOIs
Publication statusPublished - 2016

Keywords

  • Aging
  • DNA hydroxymethylation
  • TDG
  • TET genes

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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