Early mammalian erythropoiesis requires the Dot1L methyltransferase

Abstract

Histone methylation is an important regulator of gene expression; its coordinated activity is critical in complex developmental processes such as hematopoiesis. Disruptor of telomere silencing 1-like (DOT1L) is a unique histone methyltransferase that specifically methylates histone H3 at lysine 79. We analyzed Dot1L-mutant mice to determine influence of this enzyme on embryonic hematopoiesis. 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. Further, a severe, selective defect in erythroid, but not myeloid, differentiation was observed. 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. 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. 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. IntroductionAmong the first differentiated cell types to emerge in the developing mammalian embryo are the blood cells. 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. 1 By E7.5, the cells coalesce into blood islands, where they mature, proliferate, and differentiate. 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,[3][4][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. 6 After E8.5, a second wave of hematopoietic progenitors emerges from a variety of sites, including the vasculature about the aorta-gonadmesonephros and the yolk sac. These cells enter the circulation and migrate to the developing fetal liver. There, they proliferate and undergo "definitive" maturation, giving rise to multiple adult hematopoietic lineages, including mature, enucleated erythrocytes. 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. 8 The identity of the cell-type specific genes that direct differentiation, the factors controlling their expression, and...

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

“…31 Considering that mature B cells undergo FASmediated apoptosis, 32 it is reasonable to hypothesize that PLCL2 is associated with the regulation of B-cell maturation, leading to the formation of atherosclerotic lesions. DOT1L was shown to positively regulate GATA2 expression, 33 which is known to regulate the transcription of endothelial cell-specific genes. 34 In particular, DOT1L was shown to be negatively correlated with endothelin-1, 35 which has an important role in vasospasm and vasoconstriction.…”

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

“…The mammalian homolog, DOT1L, has been shown to be required for embryogenesis, hematopoiesis, and cardiac function (17)(18)(19)(20). DOT1L was recently identified as an essential and dedicated enzyme for Wnt target-gene activation in the intestine and needed for the expression of genes that require high levels of Wnt signaling in Drosophila (12, 13).…”

Silver nanoparticle-induced hemoglobin decrease involves alteration of histone 3 methylation status

“…Histone methylation is performed by histone methyltransferases that add methyl groups to histone residues, and this process is reversed by demethylases. Thus, the methylation level of lysine in histone is determined by the net activity of histone lysine methyltransferases and demethylases [43,60]. Dysfunction of these enzymes would give rise to abnormal histone methylation, possibly associated with disordered gene expression and even development of various diseases [59,61,62].…”

“…The myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2) methyltransferase complex is crucial for H3K4 trimethylation, and is necessary for the maximal transcription of the murine b-globin locus [24]. Similar to MLL2, disruptor of telomere silencing 1 (Dot-1L), a unique histone methyltransferase that specifically methylates H3 at K79, serves as a vital regulator of differentiation during early hematopoiesis [43]. MLL-rearranged leukemia is largely attributable to dysregulation of H3K79 methylation by Dot-1L [44].…”