Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells

Abstract

[Background]: Age-associated changes in genomic DNA methylation have been primarily attributed to 5-methylcytosine (5mC). However, the recent discovery of 5-hydroxymethylcytosine (5hmC) suggests that this epigenetic mark might also play a role in the process. [Methods]: Here, we analyzed the genome-wide profile of 5hmc in mesenchymal stem cells (MSCs) obtained from bone-marrow donors, aged 2-89 years. [Results]: We identified 10,685 frequently hydroxymethylated CpG sites in MSCs that were, as in other cell types, significantly associated with low density CpG regions, introns, the histone posttranslational modification H3k4me1 and enhancers. Study of the age-associated changes to 5hmC identified 785 hyper- and 846 hypo-hydroxymethylated CpG sites in the MSCs obtained from older individuals. [Conclusions]: DNA hyper-hydroxymethylation in the advanced-age group was associated with loss of 5mC, which suggests that, at specific CpG sites, this epigenetic modification might play a role in DNA methylation changes during lifetime. Since bone-marrow MSCs have many clinical applications, and the fact that the epigenomic alterations in this cell type associated with aging identified in this study could have associated functional effects, the age of donors should be taken into account in clinical settings. ; This work has been financially supported by the Plan Nacional de I + D + I 2008–2011/2013–2016/FEDER (PI11/01728 to A.F.F.; PI12/01080 and PI15/00892 to M.F.F.; PI 12/0615 to J.A.R.; PI05/2217 and PI08/0029 to J.G-C); the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Miguel Servet contract: CP11/00131 to A.F.F.); IUOPA (to G.F.B. and M.S); Fundacion Cientifica de la AECC (to R.G.U.); Fundación Ramón Areces (to M.F.F); and FICYT (to E.G.T., M.G.G and A.C.);the Madrid Regional Government (S-BIO-02042006 and S2010/BMD-2420 to J.G-C) and the Asturias Regional Government (GRUPIN14-052 to M.F.F.). The IUOPA is supported by the Obra Social Cajastur, Spain. ; Peer Reviewed