During such conditions of stress erythropoiesis, new CFU-E are produced from the most immature committed definitive erythroid progenitor cells, the BFU-E cells. The ability of BFU-E progenitors to undergo limited self-renewal during stress erythropoiesis allows rescue of lethally irradiated mice from anemia, and retransplantation also protects secondary and tertiary recipients. Early observations showed that erythropoiesis moves from the bone marrow to the spleen during stress erythropoiesis Figure 3.
BFU-E self-renewal: The probability of erythroid progenitor self-renewal versus differentiation depends on extrinsic and intrinsic factors. Although BFU-E self-renewal is very limited during steady-state erythropoiesis in the bone marrow, it is virtually limitless in the spleen during conditions of stress erythropoiesis. The cytokines Scf, Bmp4, and Shh promote self-renewal in addition, as does stimulation by GCs and hypoxia. Release of cortisol from the adrenal glands is increased during conditions of stress erythropoiesis, such as sepsis or severe trauma.
The therapeutic effect of the GC analog prednisone in patients with the RBC progenitor disorder Diamond-Blackfan anemia is well documented, although severe side effects limit its use. Mice that lack the GC receptor or express only a GC receptor defective in DNA binding and transactivation have normal steady-state erythropoiesis, whereas stress erythropoiesis is severely impaired. Identification of BFU-E as the target cell of GCs in stress erythropoiesis, together with our novel method to isolate BFU-E, will allow studies toward development of novel erythropoiesis-stimulating agents that act by promoting SE by the same mechanisms used by GCs.
SCF Kit ligand exists both in a soluble and a membrane-bound form. Kit signaling is important not only for erythroid progenitor proliferation but also for HSC growth, mast cell function, melanogenesis, and spermatogenesis. Bone morphogenetic protein 4 BMP4 is also essential for stress erythropoiesis. The flexed-tail mouse strain, which expresses a dominant-negative Smad5 mutant that inhibits BMP4 signaling, exhibits a neonatal anemia that resolves 2 weeks after birth.
These studies have provided profound insights into the multiple complex mechanisms by which the body regulates the number of RBCs within a narrow normal range. Equally importantly, they provide novel insights into possible treatments for anemias and other RBC disorders.
Furthermore, deeper understanding of mechanisms regulating BFU-E self-renewal and thus the output of CFU-E progenitors and mature erythroid cells could result in the development of drugs that stimulate the physiologic mechanisms of stress erythropoiesis.
Correspondence: Harvey F. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Extracellular signals regulating proliferation and differentiation of CFU-E progenitors.
Transcriptional regulators of erythroid proliferation and function. Epigenetic changes in chromatin during erythroid differentiation. Interplay of cell cycle and terminal erythroid differentiation. Histone deacetylation and erythroblast enucleation. Regulation of erythropoiesis by miRNAs. Article Navigation. Red Cells, Iron, and Erythropoiesis December 8, From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications Shilpa M.
Hattangadi , Shilpa M. This Site. Google Scholar. Lingbo Zhang , Lingbo Zhang. Johan Flygare , Johan Flygare. Harvey F. Lodish Harvey F. Blood 24 : — Article history Submitted:. Cite Icon Cite. Figure 1. View large Download PPT. Figure 2. Table 1 microRNAs are important regulators for erythropoiesis. Organism and experimental system. View Large. Figure 3. National Institutes of Health. Contribution: S.
Conflict-of-interest disclosure: The authors declare no competing financial interests. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Search ADS. Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR.
Thrombopoietin rescues in vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis.
Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Alpha4beta1 integrin and erythropoietin mediate temporally distinct steps in erythropoiesis: integrins in red cell development. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation.
Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Transcription factors in myeloid development: balancing differentiation with transformation. Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
Insights into GATAmediated gene activation versus repression via genome-wide chromatin occupancy analysis. The gateway to transcription: identifying, characterizing and understanding promoters in the eukaryotic genome.
Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression.
Genome-wide identification of TAL1's functional targets: insights into its mechanisms of action in primary erythroid cells. The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation.
A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. A chromatin landmark and transcription initiation at most promoters in human cells. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo.
The beta-globin locus control region LCR functions primarily by enhancing the transition from transcription initiation to elongation. TIF1gamma controls erythroid cell fate by regulating transcription elongation.
The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.
A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Differential H3K4 methylation identifies developmentally poised hematopoietic genes. Dynamics of the epigenetic landscape during erythroid differentiation after GATA1 restoration. Gene induction and repression during terminal erythropoiesis are mediated by distinct epigenetic changes. A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.
Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation. Formation of mammalian erythrocytes: chromatin condensation and enucleation.
A putative role for histone deacetylase in the differentiation of human erythroid cells. Chromatin condensation in terminally differentiating mouse erythroblasts does not involve special architectural proteins but depends on histone deacetylation.
Histone deacetylase 2 is required for chromatin condensation and subsequent enucleation of cultured mouse fetal erythroblasts. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. MicroRNAs and inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Mir selectively regulates embryonic alpha-hemoglobin synthesis during primitive erythropoiesis.
Defective erythroid differentiation in miR mutant mice mediated by zeta. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. Different stimulative effects of human bone marrow and fetal liver stromal cells on erythropoiesis in long-term culture.
Spleen stromal cell lines selectively support erythroid colony formation. Microenvironment created by stromal cells is essential for a rapid expansion of erythroid cells in mouse fetal liver. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference.
DNA binding of the glucocorticoid receptor is not essential for survival. The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors. The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit to enhance and sustain proliferation of erythroid progenitors in vitro.
Cooperative signaling between cytokine receptors and the glucocorticoid receptor in the expansion of erythroid progenitors: molecular analysis by expression profiling. The glucocorticoid receptor is a key regulator of the decision between self-renewal and differentiation in erythroid progenitors. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells.
Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen. Functional p85alpha gene is required for normal murine fetal erythropoiesis. Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. An intronic sequence mutated in flexed-tail mice regulates splicing of Smad5.
Friend virus utilizes the BMP4-dependent stress erythropoiesis pathway to induce erythroleukemia. Six members of the GATA family are known. GATA-1, -2, and -3 have roles predominantly within the hematopoietic system, whereas GATA-4, -5, and -6 are involved in non-hematopoietic tissues Orkin, Cis -acting regulatory sequences of erythroid and megakaryocyte-specific genes often contain multiple GATA DNA binding sites, and these are often situated at considerable distances from one another in promoter and enhancer elements.
This could bring distal enhancer elements into proximity of the promoter through a DNA looping mechanism. Another possibility is that FOG provides a transcriptional activation domain either by itself or via interaction with another transcriptional coactivator. This predicts that protein domains outside of the GATA-binding zinc fingers would be required for its activity.
In support of this latter model, Evans and Felsenfeld have demonstrated that GATA-1 has reduced transcriptional activity in hematopoietic cells compared to non-hematopoietic cells, suggesting that the hematopoietic environment somehow dampens GATA response Evans and Felsenfeld, Further studies will be required to elucidate the mechanism of action of FOG proteins. SCL TAL 1 , a member of the basic helix-loop-helix bHLH family of transcription factors, was first identified by its involvement in recurrent chromosomal translocations in patients with T-cell acute lymphoblastic leukemia ALL , Begley et al.
Misexpression of SCL by chromosomal translocation or other mechanisms is thought to underlie the basis for cell transformation Bash et al. These sequences are found in cis -acting regulatory elements of erythroid-specific genes in conjunction with GATA-binding motifs.
The precise role of this presumptive complex in hematopoietic development requires additional work in the future. This latter phenomenon may be due to interference with normal E protein function in T-cells. These findings further underscore the critical nature of protein-protein interactions of hematopoietic transcription factors in both normal and pathophysiologic processes. Globin gene expression is regulated in a developmentally specific pattern.
The genes that encodes these proteins are arranged on chromosome 11 in the order in which they are expressed. Each of these genes in both mice and humans is regulated by proximal cis -acting sequences. Binding sites for both EKLF and the related ubiquitously expressed protein Sp1 and GATA-1 are found in close proximity in cis -regulatory elements of erythroid-specific genes.
Thus, protein-protein interactions between EKLF and GATA-1 may be involved in facilitating the switch from fetal to adult globin expression, although there is no direct evidence to support this at this time. Since acetylation of histone proteins correlates with transcriptionally active chromatin, a simple model posits that GATA-1 recruits HAT activity through CBP to critical regions of chromatin associated with erythroid-specific genes and thereby facilitates their expression.
This may be an oversimplification, as GATA-1 protein itself is acetylated on conserved lysine residues by CBP, a modification which appears to enhance its transcriptional activity Hung et al. Mutation of the acetylated lysine residues to arginine which can not be acetylated markedly impairs GATA-1's ability to restore erythroid maturation in a GATA-1 deficient cell line, implying that this modification plays an important functional role.
The exact mechanism of this enhanced activity is controversial in that data are conflicting as to possible effects on DNA-binding Hung et al. Additional circumstantial evidence for a role of CBP in hematopoiesis has been provided by the observation that haploinsufficiency of CBP in mice leads to a bone marrow failure syndrome and a strikingly high incidence of hematologic malignancies Kung et al.
It has previously been shown that Friend virus causes murine erythroleukemia by the proviral insertion of the spleen focus forming component into the PU. This leads to dysregulated expression of PU. Additional evidence has emerged from observations that transgenic mice that overexpress PU. Conversely, ectopic expression of GATA-1 in myelomonocytic cells transforms them into erythroid, megakaryocytic and eosinophilic cells Kulessa et al.
New reports from several groups have suggested a mechanism to explain these phenomena Rekhtman et al. These investigators demonstrate that PU. Skoultchi and his colleagues have provided strong evidence for this model Rekhtman et al. They demonstrated that ectopic expression of PU. However, overexpression of GATA-1 in these cells restores normal erythroid differentiation.
As illustrated by the preceding discussion, numerous tissue-restricted transcription factors have been identified and their role in erythropoiesis validated by in vivo experimental systems. Strong evidence has been provided demonstrating that these factors participate in critical protein-protein interactions and, as such, function as multiprotein complexes. The next important step to understanding the transcriptional regulation of erythropoiesis will be to elucidate how these different complexes relate to one another.
It is reasonable to speculate that the composition of these complexes changes throughout erythroid development depending on both spatial and temporal contexts. It also seems likely that additional factors, perhaps as yet unknown, may also participate in these complexes. Perhaps the discovery of such factors will help clarify the seemingly disjointed array of complexes and facilitate a better understanding of the molecular basis of erythroid differentiation.
Classical gene-targeting techniques in mice have provided invaluable insights into the role of different transcription factors in erythropoiesis. However, these whole animal approaches by themselves are limited by the time required to generate such animals, limited biologic material in cases of embryonic lethality, inability to assess functional roles at stages past a primary block, and in vivo compensatory mechanisms that may mask effects.
New approaches are needed to complement these techniques. Cre recombinase is a bacterial enzyme that specifically catalyzes recombination at characteristic short DNA sequences referred to as loxP sites for review, see Rajewsky et al. These sequences can be inserted at regions flanking a gene or gene segment of interest using classical gene targeting approaches.
Such a system, utilizing transgenic mice expressing Cre recombinase under the control of GATA-1 regulatory sequences, has recently been employed to develop a mouse model for paroxysmal nocturnal hemoglobinuria type II Jasinski et al.
Murine ES cells can be differentiated in vitro to multipotential hematopoietic precursors as well as mature blood cells Keller et al. Retroviral expression of Hox or combinations of v-raf and v-myc have been shown to immortalize hematopoietic precursor cells derived in this manner Keller et al. These cell lines retain both growth factor dependency and differentiation capacity. Adaptation of this system using genetically modified ES cells provides cellular based assay systems in well-defined microenvironments to study hematopoietic gene function Cantor AB, Katz SG, and Orkin SH, submitted for publication; Coghill et al.
This approach offers the advantage of examining interactions in vivo and in the context of chromatinized DNA. Chromatin is cross-linked by chemical agent, sheared, and then immunoprecipitated with specific antibodies directed against the molecule of study. Cross-linking is then reversed and polymerase chain reaction used to amplify gene sequences of interest. Remarkably, many of the same transcriptional molecules used in mammalian hematopoiesis have orthologues in organisms with more rudimentary blood systems.
This provides an opportunity to exploit the powerful genetic systems already established for some of these organisms to identify novel genes and test function of known genes involved in mammalian hematopoiesis. Development of both lineages requires the drosophila GATA factor serpent. Recent work has shown that the orthologue of another mammalian transcription factor, AML-1, is required for crystal cell formation Lebestky et al.
Thus, the basic machinery of blood cell formation appears to have been well conserved throughout evolution and warrants the study of mammalian hematopoiesis in these model organisms. This occurs through the direct interaction and cross-antagonism of PU. Additional examples of cross-antagonism between lineage-specific transcription factors have begun to emerge. Pax 5, a paired domain-containing transcription factor, plays an essential role in B lymphoid development Adams et al.
However, restoration of Pax 5 expression in these cells restricts them to the B-cell lineage implying that Pax 5 represses these alternate lineage choices under normal conditions. Likewise, dissociated muscle cells from mice containing homozygous disruption of the muscle-specific Pax 7 gene produced about a fold increase in the number of hematopoietic colonies compared to cells from wildtype mice suggesting that Pax 7 may normally repress the hematopoietic lineage Seale et al.
Thus, a new view of the transcriptional regulation of hematopoietic development has begun to emerge. In contrast to a model in which lineage-specific transcription factors play principally positive roles in activating gene programs, these observations suggest that they simultaneously exert inhibitory effects on alternate lineage gene programs.
This arises through direct cross-antagonism of alternate lineage-specific transcription factors Figure 4. This paradigm may provide insight into mechanisms of maturation arrest seen in acute leukemias. Namely, misexpression of an alternate lineage-specific transcription factor through chromosomal translocation, epigenetic phenomenon, viral insertion, etc. Exploitation of these mechanisms may provide therapeutic approaches to malignancy aimed at differentiating cancer cells by manipulation of transcription factor interactions.
Thus, a better understanding of the multiple partnerships of hematopoietic transcription factors should open up new possibilities for rational drug design in the treatment of leukemias and lymphomas.
Cross-antagonistic model of lineage factor activities in hematopoietic development. Schematic representation of cell fate determination of cell types A and B from a common bipotential precursor cell. Model of transcription factor cross-antagonism and leukemia.
A Normal cell. B Leukemia cell. This blocks expression of transcription factor A target genes and produces an arrest in cell maturation. USA 86 : — USA 95 : — Cell 3 : — Evans T, Felsenfeld G. Cell Biol.
USA 98 : — USA 93 : — Goodman RH, Smolik S. Merika M, Orkin SH. USA 92 : — USA 96 : — Download references.
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