Article

Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging

Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Blood (Impact Factor: 10.43). 03/2011; 117(19):e182-9. DOI: 10.1182/blood-2011-01-331926
Source: PubMed

ABSTRACT DNA methylation plays an important role in the self-renewal of hematopoietic stem cells and in the commitment to the lymphoid or myeloid lineages. Using purified CD34⁺ hematopoietic progenitor cells and differentiated myeloid cell populations from the same human samples, we obtained detailed methylation profiles at distinct stages of hematopoiesis. We identified a defined set of differentiation-related genes that are methylated in CD34⁺ hematopoietic progenitor cells but show pronounced DNA hypomethylation in monocytes and in granulocytes. In addition, by comparing hematopoietic progenitor cells from umbilical cord blood to hematopoietic progenitor cells from peripheral blood of adult donors we were also able to analyze age-related methylation changes in CD34⁺ cells. Interestingly, the methylation changes observed in older progenitor cells showed a bimodal pattern with hypomethylation of differentiation-associated genes and de novo methylation events resembling epigenetic mutations. Our results thus provide detailed insight into the methylation dynamics during differentiation and suggest that epigenetic changes contribute to hematopoietic progenitor cell aging.

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Available from: Achim Breiling, Jul 22, 2015
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    • "Two studies have analyzed DNA methylation during aging in human adult stem cells: Bork et al. (2010) used 27K methylation arrays to analyze the DNA methylation status of mesenchymal stem cells (MSCs) obtained from young (21–50 yr) and old donors (53– 85 yr) and found similar DNA methylation changes over time during prolonged in vitro culture and in vivo aging. Using the same methylation arrays, Bocker et al. (2011) observed a bimodal pattern of methylation changes in older hematopoietic progenitor cells, with hypomethylation of differentiation-associated genes, as well as de novo methylation events resembling epigenetic mutations . Recent studies in mice have revealed a number of genomewide alterations in DNA methylation (Taiwo et al. 2013) that might play an important role in the functional decline of hematopoietic stem cells (HSCs) during aging (Beerman et al. 2013). "
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    • "Two studies have analyzed DNA methylation during aging in human adult stem cells: Bork and colleagues (Bork et al. 2010) used 27k methylation arrays to analyze the DNA methylation status of mesenchymal stem cells (MSCs) obtained from young (21–50 years) and old donors (53–85 years) and found similar DNA methylation changes over time during prolonged in vitro culture and in vivo aging. Using the same methylation arrays, Bocker and colleagues (Bocker et al. 2011) observed a bimodal pattern of methylation changes in older hematopoietic progenitor cells, with hypomethylation of differentiation-associated genes, as well as de novo methylation events resembling epigenetic mutations. Recent studies in mice have revealed a number of genome-wide alterations in DNA methylation (Taiwo et al. 2013) which might play an important role in the functional decline of hematopoietic stem cells during aging (Beerman et al. 2013). "
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    ABSTRACT: In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational 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 obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 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 non-genetic 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.
    Genome Research 09/2014; · 13.85 Impact Factor
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    • "Two studies have analyzed DNA methylation during aging in human adult stem cells: Bork and colleagues (Bork et al. 2010) used 27k methylation arrays to analyze the DNA methylation status of mesenchymal stem cells (MSCs) obtained from young (21–50 years) and old donors (53–85 years) and found similar DNA methylation changes over time during prolonged in vitro culture and in vivo aging. Using the same methylation arrays, Bocker and colleagues (Bocker et al. 2011) observed a bimodal pattern of methylation changes in older hematopoietic progenitor cells, with hypomethylation of differentiation-associated genes, as well as de novo methylation events resembling epigenetic mutations. Recent studies in mice have revealed a number of genome-wide alterations in DNA methylation (Taiwo et al. 2013) which might play an important role in the functional decline of hematopoietic stem cells during aging (Beerman et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational 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 obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 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 non-genetic 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.
    Genome Research 09/2014; 25(1). DOI:10.1101/gr.169011.113 · 13.85 Impact Factor
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