Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet

Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.
Nature Genetics (Impact Factor: 29.35). 12/2011; 44(1):23-31. DOI: 10.1038/ng.1009
Source: PubMed


Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.

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Available from: Mira Jeong, Dec 20, 2013
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    • "DNA methylation of CpG dinucleotides is catalyzed by at least three different DNA methyltransferases (DNMTs), including Dnmt1 for methylation maintenance and Dnmt3a and Dnmt3b for de novo methylation (Denis et al., 2011). The DNMTs are essential for maintaining the methylation pattern in stem cells and for regulating their self-renewal and differentiation (Challen et al., 2012; Tsai et al., 2012a). We observed downregulation of Dnmt1, Dnmt3a, and Dnmt3b in MRL/lpr BMMSCs when compared to control BMMSCs, as indicated by western blot (Figure 3A). "
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    • "We also see that HSC-specific genes such as Gata2 and Hmga2 are hypomethylated and upregulated and that binding sites of TFs associated with differentiation, such as Pu.1, tend to become hypermethylated, whereas sites associated with factors involved in stem cell function (e.g., Scl) tend to be hypomethylated . Finally, we showed that the edges of DNA methylation canyons are highly dynamic in a manner concordant with loss of Dnmt3a function (Jeong et al., 2014; Challen et al., 2012), the mutation of which is associated with hematologic malignancies (Ley et al., 2010; Yan et al., 2011). Although our data cannot distinguish cause and effect with regard to these epigenetic changes with age, together they point to a stem cell state in which self-renewal is reinforced and differentiation is impeded—a cellular milieu likely to be conducive to transformation events. "

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    • "Indeed, hypomorphic mutations in human DNMT3B lead to a rare, autosomal recessive developmental disorder: immunodeficiency, centromeric instability, facial anomalies syndrome (Hansen et al., 1999). DNMT3A is essential for hematopoietic stem cell lineage differentiation through silencing of lineage-specific genes (Challen et al., 2012). Taken together, these studies show that DNMT3A and DNMT3B mediate 5mC patterns essential for regulating distinct lineage-differentiation pathways, yet the mechanisms "
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    ABSTRACT: Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in fine detail. DNMT3B occupancy regulates methylation during differentiation, whereas an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated non-CpG methylation, whereas DNMT3L influenced the activity of DNMT3B toward non-CpG versus CpG site methylation. Altogether, these data reveal functional targets of each DNMT, suggesting that isoform selective inhibition would be therapeutically advantageous. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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