7 This multistep process of hematopoiesis and the fate decisions of the developing cells are regulated by the precisely controlled, sequential induction and silencing of gene expression in response to a variety of growth and differentiation factors. There, they proliferate and undergo “definitive” maturation, giving rise to multiple adult hematopoietic lineages, including mature, enucleated erythrocytes. These cells enter the circulation and migrate to the developing fetal liver. 6 After E8.5, a second wave of hematopoietic progenitors emerges from a variety of sites, including the vasculature about the aorta-gonad-mesonephros and the yolk sac. 1, 3, – 5 The presence of these primitive progenitors is transient, peaking in numbers at E8.0 and disappearing by E9.0, 2 whereas the progeny erythrocytes persist throughout gestation. 2 These early hematopoietic progenitors, termed primitive erythroid colony-forming cells, are nucleated red cells, which express primitive globins and can carry oxygen to nourish the developing embryo on the initiation of blood flow after E8.5. 1 By E7.5, the cells coalesce into blood islands, where they mature, proliferate, and differentiate. In the mouse, the process of blood development, hematopoiesis, begins at approximately embryonic day 7.0-7.5 (E7.0-E7.5), when cells originating in the primitive streak migrate to the site of yolk sac formation. These data suggest a model whereby DOT1L-dependent lysine 79 of histone H3 methylation serves as a critical regulator of a differentiation switch during early hematopoiesis, regulating steady-state levels of GATA2 and PU.1 transcription, thus controlling numbers of circulating erythroid and myeloid cells.Īmong the first differentiated cell types to emerge in the developing mammalian embryo are the blood cells. GATA2, a factor essential for early erythropoiesis, was significantly reduced in Dot1L-deficient cells, whereas expression of PU.1, a transcription factor that inhibits erythropoiesis and promotes myelopoiesis, was increased. Erythroid progenitors failed to develop normally, showing retarded progression through the cell cycle, accumulation during G 0/G 1 stage, and marked increase in apoptosis in response to erythroid growth factors. Further, a severe, selective defect in erythroid, but not myeloid, differentiation was observed. Mutant mice developed more slowly than wild-type embryos and died between embryonic days 10.5 and 13.5, displaying a striking anemia, especially apparent in small vessels of the yolk sac. We analyzed Dot1L-mutant mice to determine influence of this enzyme on embryonic hematopoiesis. Disruptor of telomere silencing 1-like (DOT1L) is a unique histone methyltransferase that specifically methylates histone H3 at lysine 79. Histone methylation is an important regulator of gene expression its coordinated activity is critical in complex developmental processes such as hematopoiesis.
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