Valentini Elisabetta, Zampieri Michele, Malavolta Marco, Bacalini Maria Giulia, Calabrese Roberta, Guastafierro Tiziana, Reale Anna, Franceschi Claudio, Hervonen Antti, Koller Bernhard, Bernhardt Jürgen, Slagboom P Eline, Toussaint Olivier, Sikora Ewa, Gonos Efstathios S, Breusing Nicolle, Grune Tilman, Jansen Eugène, Dollé Martijn E T, Moreno-Villanueva María, Sindlinger Thilo, Bürkle Alexander, Ciccarone Fabio, Caiafa Paola
Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy.
Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy.
Aging (Albany NY). 2016 Aug 29;8(9):1896-1922. doi: 10.18632/aging.101022.
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 , and 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.
实际上，在所有人体组织的衰老过程中，DNA甲基化格局都会发生渐进性变化。5-甲基胞嘧啶（5mC）普遍减少，并伴有高度可重复的位点特异性高甲基化，这是衰老基因组的特征。因此，在涉及DNA甲基化调控因子的一般性和定向性失调事件之间似乎存在一种平衡，这可能是与年龄相关的表观遗传变化的基础。在这种情况下，5mC羟化酶（TET酶）是新的潜在参与者。事实上，TET酶催化5mC逐步氧化为5-羟甲基胞嘧啶（5hmC）、5-甲酰基胞嘧啶（5fC）和5-羧基胞嘧啶（5caC），并基于胸腺嘧啶DNA糖基化酶（TDG）介导的DNA修复途径驱动DNA去甲基化过程。本文报道了在欧盟项目“MARK-AGE”背景下，从几个欧洲国家招募的不同年龄层供体的外周血单个核细胞中DNA羟甲基化成分的表达、5hmC及其衍生物的水平。结果为与年龄相关的 、 和 基因表达下降以及5hmC减少和5caC积累提供了证据。这些关联独立于包括招募中心、性别和白细胞组成在内的混杂变量。在血细胞中观察到的5hmC介导的DNA去甲基化途径受损可能导致老年人出现异常的转录程序。
