Bocker MT, Hellwig M, Breiling A, Eckstein V, Ho AD, Lyko F.. Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood 117: e182-e189

Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Blood (Impact Factor: 10.45). 03/2011; 117(19):e182-9. DOI: 10.1182/blood-2011-01-331926
Source: PubMed


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
    • "Subsequently, de novo DNA methylation of dividing cells establishes the CpG methylation marks that guide restriction of gene expression patterns associated with tissue-specific lineages (Smith et al. 2012). In adult tissues, CpG methylation marks must also be maintained by DNA methyl-transferases during DNA replication to preserve the identity and function of differentiating cell types and for self-renewal of adult stem cell populations (Trowbridge and Orkin 2010;Bocker et al. 2011; Berdasco and Esteller 2010). Taking only into account the information content of alternatively spliced sites (ASSs) with consensus sequences like 5′ splice sites, 3′ splice sites, and branch sites is insufficient for splice site selection (). "
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    ABSTRACT: Gene promoters are essential regions of DNA where the transcriptional molecular machinery to produce RNA molecules is recruited. In this process, DNA epigenetic modifications can acquire a fundamental role in the regulation of gene expression. Recently, in a previous work of our group, functional features and DNA methylation involved in the ovine HSP90AA1 gene expression regulation have been observed. In this work, we report a combination of methylation analysis by bisulfite sequencing in several tissues and at different developmental stages together with in silico bioinformatic analysis of putative regulating factors in order to identify regulative mechanisms both at the promoter and gene body. Our results show a “hybrid structure” (TATA box + CpG island) of the ovine HSP90AA1 gene promoter both in somatic and non-differentiated germ tissues, revealing the ability of the HSP90AA1 gene to be regulated both in an inducible and constitutive fashion. In addition, in silico analysis showed that several putative alternative spliced regulatory motifs, exonic splicing enhancers (ESEs), and G-quadruplex secondary structures were somehow related to the DNA methylation pattern found. The results obtained here could help explain the differences in cell-type transcripts, tissue expression rate, and transcription silencing mechanisms found in this gene.
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    • "This indicates that muscle stem cells do not lose their differentiation potency with age, suggesting that the decrease with aging in the differentiation program during muscle regeneration is strongly related to changes in circulating factors. DNA methylation has been shown to be increased in several tissues with aging, and the skeletal muscle is no exception [119] [120]. We have observed a higher level of DNA methylation in satellite cells of aged subjects (unpublished data). "
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    ABSTRACT: Aging is associated with both muscle weakness and a loss of muscle mass, contributing towards overall frailty in the elderly. Aging skeletal muscle is also characterised by a decreasing efficiency in repair and regeneration, together with a decline in the number of adult stem cells. Commensurate with this are general changes in whole body endocrine signalling, in local muscle secretory environment, as well as in intrinsic properties of the stem cells themselves. The present review discusses the various mechanisms that may be implicated in these age-associated changes, focusing on aspects of cell-cell communication and long-distance signalling factors, such as levels of circulating growth hormone, IL-6, IGF1, sex hormones, and inflammatory cytokines. Changes in the local environment are also discussed, implicating IL-6, IL-4, FGF-2, as well as other myokines, and processes that lead to thickening of the extra-cellular matrix. These factors, involved primarily in communication, can also modulate the intrinsic properties of muscle stem cells, including reduced DNA accessibility and repression of specific genes by methylation. Finally we discuss the decrease in the stem cell pool, particularly the failure of elderly myoblasts to re-quiesce after activation, and the consequences of all these changes on general muscle homeostasis.
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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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