Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.

  title={Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.},
  author={Joachim Fandrey},
  journal={American journal of physiology. Regulatory, integrative and comparative physiology},
  volume={286 6},
  • J. Fandrey
  • Published 1 June 2004
  • Biology
  • American journal of physiology. Regulatory, integrative and comparative physiology
Hypoxia-inducible expression of the gene encoding for the glycoprotein hormone erythropoietin (EPO) is the paradigm of oxygen-regulated gene expression. EPO is the main regulator of red blood cell production and more than 100 years of research on the regulation of EPO production have led to the identification of a widespread cellular oxygen sensing mechanism. Central to this signaling cascade is the transcription factor complex hypoxia-inducible factor-1 (HIF-1). Meanwhile, it is known that HIF… 

Figures from this paper


In humans and other mammals, hypoxia modulates EPO levels by increasing expression of the EPO gene, and the HIF system is implicated in the pathophysiology of many human diseases.

Nonrenal regulation of EPO synthesis.

An overview of the molecular aspects ofEPO gene regulation by hypoxia-inducible transcription factors and of the tissue-specific regulation of EPO production in adult mammals is provided.

Oxygen-regulated expression of the erythropoietin gene in the human renal cell line REPC.

The human kidney cell line REPC (for renal Epo-producing cells), established from an explanted human kidney exhibiting EPO gene expression and release of the EPO protein in an oxygen-dependent manner, is presented for the first time.

Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis

Additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis are investigated, including genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport.

Herpesvirus entry mediator regulates hypoxia-inducible factor-1α and erythropoiesis in mice.

Signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions, suggesting this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.

Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.

Evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes is provided, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis.

Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.

Conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia is shown, providing genetic evidence that HIF-1 and H IF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIFs in the liver.

Oxygen-dependent Regulation of Transcription by the Hypoxia-inducible Factor-1

Evidence is provided that, under hypoxic conditions, the high affinity of HIF-1α for limiting amounts of CBP, may interfere with other CBP-dependent pathways.

List of contributors

Evidence of EPO as a protective factor in various injury models in the nervous system and heart has raised the possibility that EPO can exert protective effects in many organs in the body, however, whether the mechanism of protective action involves inhibition of apoptosis remains to be seen.

Hypoxic regulation of erythropoiesis and iron metabolism.

  • V. Haase
  • Biology, Medicine
    American journal of physiology. Renal physiology
  • 2010
Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.



Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein.

A model is proposed in which a ligand-dependent conformational change in a heme protein accounts for the mechanism by which hypoxia as well as cobalt and nickel stimulate the production of Epo.

Hypoxic Regulation of Lactate Dehydrogenase A

To understand the organization of cis-acting sequences that are responsible for oxygen-regulated gene expression, the 5′ flanking region of the mouse gene encoding the hypoxically inducible enzyme lactate dehydrogenase A (LDH) is studied.

A new transacting factor that modulates hypoxia-induced expression of the erythropoietin gene.

In Hep3B cells, clones modified to express HAF antisense RNA showed an attenuated response to hypoxia-mediated induction of both erythropoietin and vascular endothelial growth factor transcription.

Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys.

The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of Hif-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles.

Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism.

It is shown that an oxygen-sensing system similar, or identical, to that controlling erythropoietin expression is wide-spread in mammalian cells and mediates other adaptive responses to hypoxia.

Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.

It is demonstrated that HIF-1alpha is a master regulator of cellular and developmental O2 homeostasis in Hif1a-/- embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme.

Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus.

Ovariectomized mice were given E(2) and/or exposed to hypoxia, and temporal patterns of Epo mRNA levels were examined, indicating that downregulation operates in the kidney but not in the brain.

Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site.

It is found that methylation of the HBS abolishes Hif-1 DNA binding as well as hypoxic reporter gene activation, suggesting that a methylation-free HBS is mandatory for HIF-1 function.

Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure.

Results indicate that tissue hypoxia and cobalt exposure specifically enhance erythropoietin gene expression, which is regulated at least in part at the level of gene transcription.

Negative regulation of the erythropoietin gene expression by the GATA transcription factors.

It is concluded that the hGATA-1, 2, and 3 transcription factors specifically bind to the GATA element in the human Epo gene promoter and negatively regulateEpo gene expression.