From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

Abstract

This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burstforming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress.We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis. (Blood. 2011;118(24): 6258-6268) IntroductionIn mammals, definitive erythropoiesis first occurs in the fetal liver with progenitor cells from the yolk sac. 1 Within the fetal liver and the adult bone marrow, hematopoietic cells are formed continuously from a small population of pluripotent stem cells that generate progenitors committed to one or a few hematopoietic lineages (Figure 1). In the erythroid lineage, the earliest committed progenitors identified ex vivo are the slowly proliferating burstforming unit-erythroid (BFU-E). Early BFU-E cells divide and further differentiate through the mature BFU-E stage into rapidly dividing colony-forming unit-erythroid (CFU-E). 2 CFU-E progenitors divide 3 to 5 times over 2 to 3 days as they differentiate and undergo many substantial changes, including a decrease in cell size, chromatin condensation, and hemoglobinization, leading up to their enucleation and expulsion of other organelles. 3 In humans, the life span of RBCs is 120 days. Under normal conditions, approximately 1% of RBCs are synthesized each day but RBC production can increase substantially during times of acute or chronic stress, such as acute trauma or hemolysis. Exquisite short-term control of erythropoiesis is regulated by the kidney-derived cytokine erythropoietin (Epo), which is induced under hypoxic conditions and stimulates the terminal proliferation and differentiation of CFU-E progenitors. 4 BFU-E cells respond to many hormones in addition to Epo, including SCF, insulin like growth factor 1 (IGF-1), glucocorticoids (GCs), and IL-3, and IL-6. In cases of chronic erythroid stress, such as hemolysis, the number of CFU-E progenitors is insufficient to produce the needed RBCs, even under high Epo levels, and the body responds by producing more of these progenitors from BFU-E. 5 It is not entirely known which cells in the fetal liver or adult bone marrow produce these and other regulatory cytokines, or how they interact to regulate the division of BFU-E cells and control their self-renewal and their ability to differentiate into more mature CFU-E progenitors.At each stage of RBC production, intracellular signal transduction proteins and transcription factors activated downstream of these hormones interact with a group of DNA-binding and other transcription factors and chromati...

Establishing a hematopoietic genetic network through locus-specific integration of chromatin regulators

“…Erythrocyte development requires cell-intrinsic and -extrinsic mechanisms that control commitment of multipotent hematopoietic precursors, massive gene-expression changes, and sequential maturation steps, including gross organelle remodeling, that prepare for enucleation (1,44,51). Analogous to GATA-1, FOG-1 is a master regulator of erythropoiesis with broad roles to establish the erythroid cell phenotype.…”

“…Given the crucial red blood cell functions and common therapeutic scenarios demanding modulation of erythropoiesis (1), it is instructive to consider how epigenetic mechanisms control hematopoietic stem cell (HSC) differentiation into multipotent progenitors, lineage-committed progenitors, and ultimately erythrocytes. The transcription factor GATA-2 (2, 3) is required for the genesis and maintenance of HSCs (4), whereas GATA-1 (5, 6) is crucial for erythrocyte, megakaryocyte, mast cell, and eosinophil development (7,8).…”

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

“…With regard to this specific type of histone modification, H3K4me3, a typical marker within H3 tail, correlates with transcriptional activation [25], and has been reported to have a significant role in enhancing the transcription of the coding region of the active b maj -globin gene during erythroid differentiation for MEL cells [24]. In addition, compared to monoand dimethylation, the trimethylation of H3K4 is more associated with gene activation in vivo [45].…”

“…Transcription of b-globin was activated by increased methylation at K4 and K79 of H3 [21,24,25]. However, little is known about the influence of AgNPs on b-globin transcription through epigenetic regulations thus far.…”

Inactivation of 3- hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy

“…In erythropoiesis, pluripotent hematopoietic stem cells give rise to committed erythroid progenitor cells and to additional progenitors and precursors (6). The earliest committed erythroid progenitor is the burst-forming unit erythroid, which differentiates to produce CFU-erythroid (7).…”