Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process
Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process
复制标题
DOI：
10.1093/gerona/glw185
复制
发表时间：
2017-08-01
影响因子：
5.1
通讯作者：
Garagnani, Paolo
中科院分区：
文献类型：
--
作者：
Bacalini, Maria Giulia;Deelen, Joris;Garagnani, Paolo
表观重塑是衰老过程的主要特征之一。我们最近证实，ELOVL2和FHL2 CpG岛的DNA甲基化与全血中的年龄高度相关。在这里，我们研究了与年龄相关的ELOVL2和FHL2高甲基化的几个方面。我们发现不同年龄的供者在原代培养的真皮成纤维细胞中ELOVL2甲基化显著不同。利用来自公共资源的表观基因组数据，我们证明了大多数组织随着年龄的增长表现出ELOVL2和FHL2超甲基化。有趣的是，在复制率非常低的组织中没有发现ELOVL2超甲基化。我们证明ELOVL2高甲基化与体外细胞复制有关，而不是与衰老有关。在Doetinchem队列研究的纵向评估参与者中，我们证实了ELOVL2和FHL2的个体内超甲基化。最后，我们发现，尽管在莱顿长寿研究中，这两个基因的甲基化与寿命/死亡率无关，但ELOVL2甲基化与非老年人群中巨细胞病毒的状态有关，这可能是部分全血细胞中复制事件数量较多的信息。总的来说，这些结果表明ELOVL2甲基化是人类衰老过程中细胞分裂的一个标志。
Epigenetic remodeling is one of the major features of the aging process. We recently demonstrated that DNA methylation of ELOVL2 and FHL2 CpG islands is highly correlated with age in whole blood. Here we investigated several aspects of age-associated hypermethylation of ELOVL2 and FHL2. We showed that ELOVL2 methylation is significantly different in primary dermal fibroblast cultures from donors of different ages. Using epigenomic data from public resources, we demonstrated that most of the tissues show ELOVL2 and FHL2 hypermethylation with age. Interestingly, ELOVL2 hypermethylation was not found in tissues with very low replication rate. We demonstrated that ELOVL2 hypermethylation is associated with in vitro cell replication rather than with senescence. We confirmed intra-individual hypermethylation of ELOVL2 and FHL2 in longitudinally assessed participants from the Doetinchem Cohort Study. Finally we showed that, although the methylation of the two loci is not associated with longevity/mortality in the Leiden Longevity Study, ELOVL2 methylation is associated with cytomegalovirus status in nonagenarians, which could be informative of a higher number of replication events in a fraction of whole-blood cells. Collectively, these results indicate that ELOVL2 methylation is a marker of cell divisions occurring during human aging.