Fernández Agustín F, Bayón Gustavo F, Urdinguio Rocío G, Toraño Estela G, García María G, Carella Antonella, Petrus-Reurer Sandra, Ferrero Cecilia, Martinez-Camblor Pablo, Cubillo Isabel, García-Castro Javier, Delgado-Calle Jesús, Pérez-Campo Flor M, Riancho José A, Bueno Clara, Menéndez Pablo, Mentink Anouk, Mareschi Katia, Claire Fabian, Fagnani Corrado, Medda Emanuela, Toccaceli Virgilia, Brescianini Sonia, Moran Sebastián, Esteller Manel, Stolzing Alexandra, de Boer Jan, Nisticò Lorenza, Stazi Maria A, Fraga Mario F
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain;
Oficina de Investigación Biosanitaria (OIB-FICYT) de Asturias, 33005 Oviedo, Spain and Universidad Autónoma de Chile, Chile;
Genome Res. 2015 Jan;25(1):27-40. doi: 10.1101/gr.169011.113. Epub 2014 Sep 30.
In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.
在分化细胞中，衰老与富含抑制性组蛋白翻译后修饰的DNA区域的高甲基化有关。然而，在成体干细胞一生中与DNA甲基化变化相关的染色质标记仍大多未知。在此，对从2岁至92岁个体获取的间充质干细胞（MSC）进行DNA甲基化分析，鉴定出18735个与衰老相关的高甲基化CpG位点和45407个低甲基化CpG位点。与分化细胞一样，高甲基化序列富含染色质抑制标记。最重要的是，低甲基化CpG位点在干细胞和分化细胞的活性染色质标记H3K4me1中强烈富集，表明这是衰老过程中DNA低甲基化的一种不依赖细胞类型的染色质特征。异方差分析表明，间充质干细胞和分化细胞在衰老过程中DNA甲基化的个体间变异性增加，为识别随时间变化的DNA甲基化变化提供了一条新途径。对基因相同个体的DNA甲基化分析表明，DNA甲基化变化的趋势和异方差性均取决于非遗传因素以及遗传因素。我们的结果表明，衰老过程中DNA甲基化的动态变化取决于多种复杂因素的组合，这些因素包括所涉及的DNA序列、细胞类型和染色质背景，并且根据基因座的不同，这些变化可由遗传和/或外部因素调节。
