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Hypoxia, Erythropoietin Gene Expression, and Erythropoiesis

Peter J. Ratcliffe, Kai‐Uwe Eckardt, Christian Bauer

10.1002/cphy.cp040249

Source: Supplement 14: Handbook of Physiology, Environmental Physiology

Originally published: 1996

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 null
1.1 The Functional Anatomy of the Erythropoietin Molecule
2 The Erythropoietin Receptor
3 Erythropoiesis and Erythroid Differentiation
4 Modulation of Serum Erythropoietin Levels
4.1 Assays for Erythropoietin
4.2 Serum Erythropoietin Levels and Their Dependence on Oxygenation
4.3 Kinetics and Quantity of Increases in Serum Erythropoietin Levels
4.4 Disturbances in Oxygen‐Dependent Control of Serum Erythropoietin Levels
4.5 Clearance and Metabolic Fate of Erythropoietin
5 The Source of Erythropoietin
5.1 Organs Producing Erythropoietin
5.2 Relative Contribution of Liver and Kidneys to Erythropoietin Formation
5.3 Cellular Site of Erythropoietin Formation
6 Oxygen Sensing in the Control of Erythropoietin Formation
6.1 Evidence for Intrarenal Oxygen Sensing
6.2 The Role of Local Oxygenation in Hepatic Erythropoietin Formation
6.3 The Role of Local Oxygenation for Renal Erythropoietin Formation
6.4 Mechanism of Oxygen Sensing and Signal Transduction
7 Control of Erythropoietin Gene Expression
7.1 Modulation of Erythropoietin mRNA Levels
7.2 Cis‐Acting Sequences that Coordinate Gene Expression
7.3 Sequence Conservation in Erythropoietin Genes
7.4 Hypersensitive Sites in Erythropoietin Genes
7.5 The Promoter of the Erythropoietin Gene
7.6 Enhancer Elements 3′ to the Erythropoietin Gene
7.7 Operation of Distant Cis‐Acting Elements to Control Tissue Specificity of Gene Expression
7.8 Cis‐Acting Sequences in Erythropoietin mRNA
8 Relationship to other Adaptive Responses to Hypoxia
Figure 1. Figure 1.

Secondary and tertiary structure prediction for a group of GRH‐like cytokines, (a) Location of secondary structural elements in the human sequences for GRH, PRL, IL‐6, G‐CSF, and EPO. The four α helices from the GRH X‐ray structure are labeled A to D; loops between helices are appropriately named. Known disulfide bridge connections are marked in black lines. Gene exon boundaries are indicated beneath the respective protein sequences by black triangles, (b) Drawing of the GRH fold emphasizing the helix bundle core and loop connectivity. The exposed surface of helix D will play an important role in receptor binding

from ref. 11, with permission
Figure 2. Figure 2.

The relation between hemoglobin and serum erythropoietin in patients without renal disease (closed circles), patients with a functioning renal transplant (closed squares), and patients with anemia associated with renal failure managed by dialysis (nephric (open circles) and anephric (open squares) subjects)

from ref. 41, with permission
Figure 3. Figure 3.

Changes with development in the total amount of erythropoietin mRNA in rat kidney (closed symbols) and livers (open symbols). Erythropoietin mRNA was quantified by RNAse protection assays; units are arbitrary and relate values to a standard preparation of erythropoietin mRNA. Before 28 days the liver contains the majority of total‐body erythropoietin mRNA. Although renal erythropoietin mRNA increases with development and exceeds the hepatic contribution, the liver still contains approximately 33% of the total erythropoietin mRNA in severe stimulated animals. This contribution is similar whether stimulation is by normobaric hypoxia or exposure to carbon monoxide

from ref. 66, with permission
Figure 4. Figure 4.

Schematic diagram of the erythropoietin gene indicating the position of possible cis‐acting control regions. The gene consists of five exons (boxed areas) and four introns (not drawn to scale). The exonic regions contain long 5′ and 3′ untranslated region (open boxes) lying on either side of coding sequence (hatched boxes). Features indicated on the diagram are (i) the transcriptional start site, (ii) translation initiation, (iii) the stop codon, (iv) the poly A addition site, (v) the existence of distant sequence lying 5′ to the gene, which acts to control tissue specificity of expression and possibly as an inducible element in kidney (Fig. 4, (vi) the promoter region, (vii) the 1st intron, which is unusually highly conserved, (viii) the position in the 3′ untranslated region of an mRNA protein binding site (Fig. 4, (ix) the position of a transcriptional enhancer lying 3′ to the poly A addition site (Fig. 4d,e).

Northern blot analysis of expression of human erythropoietin mRNA in the organs of an anemic transgenic mouse bearing a 22 kb human erythropoietin transgene. Organs are brain (Br), heart (He), intestine (In), kidney (Ki), liver (Li), lung (Lu), spleen (Sp), testes (Te), and thymus (Th). Expression pattern mimics that of the endogenous gene in that expression is limited to the liver and kidney. Comparison of this expression pattern with that of human erythropoietin transgenes of different lengths in other lines of transgenic mice indicates the existence of a region between 6 and 14 kb 5′ to the human erythropoietin gene that is required for regulated expression in kidney

Demonstration of erythropoietin mRNA protein complexes by band‐shift assays. (A) A restriction map of the full‐length erythropoietin cDNA. Transcripts running to the indicated restriction sites were generated using SP6 RNA polymerase after linearization of the template at each of those restriction sites. (B) Autoradiograph of band‐shift assay using cytosolic lysates from normoxic Hep3B cells. The arrow designates the erythropoietin RNA band‐shifted complex, while the bracket represents free RNA. Complex formation is not observed when the transcripts stop at the Stu I or KpnI sites, indicating a binding site in the 3′ UTR

Demonstration of hypersensitive sites lying 3′ to the human erythropoietin gene. Nuclei were prepared from liver and kidney of transgenic mice containing six copies of a 10 kb human transgene lying head to tail (two are shown in the diagram). This created an internal Bgl2 restriction fragment (4.4 kb). When nuclei were treated with the indicated amounts of DNAse I (μg/ml) prior to DNA extraction and Bgl2 digestion, cleavage occurred in the liver nuclei to create the additional 0.6 and 0.5 kb fragments. The position of this site is indicated by a vertical arrow and correlates with the functional demonstration of an enhancer element

Operation of the erythropoietin 3′ enhancer in transiently transfected HepG2 cells. Portions of the mouse erythropoietin gene were coupled to a human α globin gene and tested for their ability to convey hypoxic regulation on the α globin reporter. (a) Position of the linked human α globin and mouse erythropoietin gene in the recombinant test plasmids. (b) Autoradiograph of RNAse protection assay. Alternate lanes show normoxic and hypoxic α globin expression and expression of the control plasmid containing a ferritin‐growth homrone fusion gene (FGH). The erythropoietin gene fragments for each test plasmid are indicated above each lane. The presence of the Apa1‐Pvu 2 fragment containing the active enhancer sequence is indicated below the autoradiograph, and its orientation with respect to the α globin gene is indicated as + or ‐. The element conveys oxygen‐regulated expression independently of distance or orientation with respect to the α1‐globin promoter

from ref. 240, with permissionfrom ref. 241, with permissionfrom ref. 213, with permission
Figure 5. Figure 5.

In transfected cells the oxygen‐dependent operation of the erythropoietin 3′ enhancer is more widespread than expression of the native erythropoietin gene. (a) Autoradiograph of RNAse protection assay showing oxygen‐dependent operation of the erythropoietin 3′ enhancer in transfected MRC5 and HepG2. Alternate lanes show normoxic and hypoxic expression of the test plasmids containing α globin with or without the erythropoietin 3′ enhancer. A ferritin—growth hormone fusion gene was used on the cotransfected control plasmid. A similar increase in transcription of the α globin reporter gene is observed in hypoxic cells of each type when the enhancer is present. (b) Autoradiograph of RNAse protection assay of endogenous erythropoietin gene expression in MRC5 (human lung fibroblast cell line) and HepG2 (human hepatoma cell line). Endogenous erythropoietin gene expression is seen in HepG2 but not MRC5.


Figure 1.

Secondary and tertiary structure prediction for a group of GRH‐like cytokines, (a) Location of secondary structural elements in the human sequences for GRH, PRL, IL‐6, G‐CSF, and EPO. The four α helices from the GRH X‐ray structure are labeled A to D; loops between helices are appropriately named. Known disulfide bridge connections are marked in black lines. Gene exon boundaries are indicated beneath the respective protein sequences by black triangles, (b) Drawing of the GRH fold emphasizing the helix bundle core and loop connectivity. The exposed surface of helix D will play an important role in receptor binding

from ref. 11, with permission


Figure 2.

The relation between hemoglobin and serum erythropoietin in patients without renal disease (closed circles), patients with a functioning renal transplant (closed squares), and patients with anemia associated with renal failure managed by dialysis (nephric (open circles) and anephric (open squares) subjects)

from ref. 41, with permission


Figure 3.

Changes with development in the total amount of erythropoietin mRNA in rat kidney (closed symbols) and livers (open symbols). Erythropoietin mRNA was quantified by RNAse protection assays; units are arbitrary and relate values to a standard preparation of erythropoietin mRNA. Before 28 days the liver contains the majority of total‐body erythropoietin mRNA. Although renal erythropoietin mRNA increases with development and exceeds the hepatic contribution, the liver still contains approximately 33% of the total erythropoietin mRNA in severe stimulated animals. This contribution is similar whether stimulation is by normobaric hypoxia or exposure to carbon monoxide

from ref. 66, with permission


Figure 4.

Schematic diagram of the erythropoietin gene indicating the position of possible cis‐acting control regions. The gene consists of five exons (boxed areas) and four introns (not drawn to scale). The exonic regions contain long 5′ and 3′ untranslated region (open boxes) lying on either side of coding sequence (hatched boxes). Features indicated on the diagram are (i) the transcriptional start site, (ii) translation initiation, (iii) the stop codon, (iv) the poly A addition site, (v) the existence of distant sequence lying 5′ to the gene, which acts to control tissue specificity of expression and possibly as an inducible element in kidney (Fig. 4, (vi) the promoter region, (vii) the 1st intron, which is unusually highly conserved, (viii) the position in the 3′ untranslated region of an mRNA protein binding site (Fig. 4, (ix) the position of a transcriptional enhancer lying 3′ to the poly A addition site (Fig. 4d,e).

Northern blot analysis of expression of human erythropoietin mRNA in the organs of an anemic transgenic mouse bearing a 22 kb human erythropoietin transgene. Organs are brain (Br), heart (He), intestine (In), kidney (Ki), liver (Li), lung (Lu), spleen (Sp), testes (Te), and thymus (Th). Expression pattern mimics that of the endogenous gene in that expression is limited to the liver and kidney. Comparison of this expression pattern with that of human erythropoietin transgenes of different lengths in other lines of transgenic mice indicates the existence of a region between 6 and 14 kb 5′ to the human erythropoietin gene that is required for regulated expression in kidney

Demonstration of erythropoietin mRNA protein complexes by band‐shift assays. (A) A restriction map of the full‐length erythropoietin cDNA. Transcripts running to the indicated restriction sites were generated using SP6 RNA polymerase after linearization of the template at each of those restriction sites. (B) Autoradiograph of band‐shift assay using cytosolic lysates from normoxic Hep3B cells. The arrow designates the erythropoietin RNA band‐shifted complex, while the bracket represents free RNA. Complex formation is not observed when the transcripts stop at the Stu I or KpnI sites, indicating a binding site in the 3′ UTR

Demonstration of hypersensitive sites lying 3′ to the human erythropoietin gene. Nuclei were prepared from liver and kidney of transgenic mice containing six copies of a 10 kb human transgene lying head to tail (two are shown in the diagram). This created an internal Bgl2 restriction fragment (4.4 kb). When nuclei were treated with the indicated amounts of DNAse I (μg/ml) prior to DNA extraction and Bgl2 digestion, cleavage occurred in the liver nuclei to create the additional 0.6 and 0.5 kb fragments. The position of this site is indicated by a vertical arrow and correlates with the functional demonstration of an enhancer element

Operation of the erythropoietin 3′ enhancer in transiently transfected HepG2 cells. Portions of the mouse erythropoietin gene were coupled to a human α globin gene and tested for their ability to convey hypoxic regulation on the α globin reporter. (a) Position of the linked human α globin and mouse erythropoietin gene in the recombinant test plasmids. (b) Autoradiograph of RNAse protection assay. Alternate lanes show normoxic and hypoxic α globin expression and expression of the control plasmid containing a ferritin‐growth homrone fusion gene (FGH). The erythropoietin gene fragments for each test plasmid are indicated above each lane. The presence of the Apa1‐Pvu 2 fragment containing the active enhancer sequence is indicated below the autoradiograph, and its orientation with respect to the α globin gene is indicated as + or ‐. The element conveys oxygen‐regulated expression independently of distance or orientation with respect to the α1‐globin promoter

from ref. 240, with permissionfrom ref. 241, with permissionfrom ref. 213, with permission


Figure 5.

In transfected cells the oxygen‐dependent operation of the erythropoietin 3′ enhancer is more widespread than expression of the native erythropoietin gene. (a) Autoradiograph of RNAse protection assay showing oxygen‐dependent operation of the erythropoietin 3′ enhancer in transfected MRC5 and HepG2. Alternate lanes show normoxic and hypoxic expression of the test plasmids containing α globin with or without the erythropoietin 3′ enhancer. A ferritin—growth hormone fusion gene was used on the cotransfected control plasmid. A similar increase in transcription of the α globin reporter gene is observed in hypoxic cells of each type when the enhancer is present. (b) Autoradiograph of RNAse protection assay of endogenous erythropoietin gene expression in MRC5 (human lung fibroblast cell line) and HepG2 (human hepatoma cell line). Endogenous erythropoietin gene expression is seen in HepG2 but not MRC5.

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Article Title: Hypoxia, Erythropoietin Gene Expression, and Erythropoiesis
 

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Peter J. Ratcliffe, Kai‐Uwe Eckardt, Christian Bauer. Hypoxia, Erythropoietin Gene Expression, and Erythropoiesis. Compr Physiol 2011, Supplement 14: Handbook of Physiology, Environmental Physiology: 1125-1153. First published in print 1996. doi: 10.1002/cphy.cp040249