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

Abstract

BackgroundAge-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.MethodsHere, we analyzed the genome-wide profile of 5hmc in mesenchymal stem cells (MSCs) obtained from bone-marrow donors, aged 2–89 years.ResultsWe 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.ConclusionsDNA 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0966-x) contains supplementary material, which is available to authorized users.

Non-canonical aberrant DNA hypermethylation in glioma

“…Interestingly, 5hmC co-localized in regions marked with the activating histone PTM H3K4me1. This histone mark has been previously associated with gene enhancers [20; 48], which suggests that DNA hydroxymethylation might play a role in gene regulation in trans. Moreover, we have recently found an association between H3K4me1 and DNA hypomethylation during aging in stem and differentiated cells [12], which may represent an interesting link between aging and cancer at these genomic regions.…”

Methylome Analysis of Human Bone Marrow MSCs Reveals Extensive Age- and Culture-Induced Changes at Distal Regulatory Elements

“…On caveat of our study, and others like it, is that bisulfite conversion does not distinguish between 5mC and 5hmC (hydroxymethylation). A recent study found approximately 1,600 age-associated 5hmC changes in BM-MSCs ( Toraño et al., 2016 ). The 5hmC state has not shown to be repressive, and it is likely not to impact TF binding.…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…In a similar way, regulated and reproducible DNA methylation changes occur during in vitro replicative senescence and can be used to monitor senescence of cell preparations [81,82,84]. Another epigenetic modification of DNA bases is represented by 5-hydroxymethylcytosine (5hmC), recently proposed as additional epigenetic age-related biomarker, associated to 5 methylcytosine (5mC) loss [85].…”

“…Histone H3/H4 acetylation is significantly reduced with advancing culture passages in association with enhanced global histone deacetylase activity [77,144]. In general, there is a gradual decrease in global DNA methylation with MSC aging in culture [2,85,145]. Hypomethylated regions are preferentially localized in genes related to morphogenesis and prevail over hypermethylated ones, enriched in genes associated with differentiation [76].…”