RESUMO
Abstract Aging is associated with the deterioration of biological functions, which is either caused by accumulation of random defects or mediated by a controlled process. This article provides an overview of age-associated epigenetic alterations in the histone code, DNA-methylation (DNAm) pattern, and chromatin structure. In particular, age-related DNAm changes are highly reproducible at specific sites in the genome. The DNAm level at few CpGs facilitates estimation of chronological age and there is evidence that such predictions are indicative for biological age. Overall, aging appears to be associated with a tightly regulated epigenetic process, but the underlying mechanism remains to be elucidated.
Assuntos
Envelhecimento , Epigênese Genética , Animais , Cromatina/genética , Cromatina/metabolismo , DNA/genética , DNA/metabolismo , Metilação de DNA , Histonas/genética , Histonas/metabolismo , HumanosRESUMO
BACKGROUND: Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. RESULTS: We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs--located in the genes ITGA2B, ASPA and PDE4C--were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita--two diseases associated with progressive bone marrow failure and severe telomere attrition--are predicted to be prematurely aged. CONCLUSIONS: Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.
Assuntos
Envelhecimento/genética , Senescência Celular/genética , Metilação de DNA/genética , Epigênese Genética , Amidoidrolases/genética , Células Sanguíneas , Ilhas de CpG/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Genoma Humano , Humanos , Células-Tronco Pluripotentes Induzidas , Integrina alfa2/genéticaRESUMO
Hematopoietic stem and progenitor cells (HPCs) can be maintained in vitro, but the vast majority of their progeny loses stemness during culture. In this study, we compared DNA-methylation (DNAm) profiles of freshly isolated and culture-expanded HPCs. Culture conditions of CD34(+) cells - either with or without mesenchymal stromal cells (MSCs) - had relatively little impact on DNAm, although proliferation is greatly increased by stromal support. However, all cultured HPCs - even those which remained CD34(+) - acquired significant DNA-hypermethylation. DNA-hypermethylation occurred particularly in up-stream promoter regions, shore-regions of CpG islands, binding sites for PU.1, HOXA5 and RUNX1, and it was reflected in differential gene expression and variant transcripts of DNMT3A. Low concentrations of DNAm inhibitors slightly increased the frequency of colony-forming unit initiating cells. Our results demonstrate that HPCs acquire DNA-hypermethylation at specific sites in the genome which is relevant for the rapid loss of stemness during in vitro manipulation.