Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing

Xu Zhang, Wei Zhang, Shwu Fan Ma, Galina Miasniakova, Adelina Sergueeva, Tatiana Ammosova, Min Xu, Sergei Nekhai, Mehdi Nourai, Michael S. Wade, Josef T. Prchal, Joe G.N. Garcia, Roberto F. Machado, Victor R. Gordeuk

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

In congenital Chuvash polycythemia (CP), VHLR200W homozygosity leads to elevated hypoxia inducible factor (HIF) levels at normoxia. CP is often treated by phlebotomy resulting in iron deficiency, permitting us to examine the separate and synergistic effects of iron deficiency and HIF signaling on gene expression. We compared peripheral blood mononuclear cell gene expression profiles of eight VHLR200W homozygotes with 17 wildtype individuals with normal iron status and found 812 up-regulated and 2120 down-regulated genes at false discovery rate of 0.05. Among differential genes we identified three major gene regulation modules involving induction of innate immune responses, alteration of carbohydrate and lipid metabolism, and down-regulation of cell proliferation, stress-induced apoptosis and T-cell activation. These observations suggest molecular mechanisms for previous observations in CP of lower blood sugar without increased insulin and low oncogenic potential. Studies including 16 additional VHLR200W homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHLR200W for 50 genes including hemoglobin synthesis loci but suppressed the effect for 107 genes enriched for HIF-2 targets. This pattern is consistent with potentiation of HIF-1α protein stability by iron deficiency but a trend for down-regulation of HIF-2α translation by iron deficiency overriding an increase in HIF-2α protein stability.

Original languageEnglish (US)
Pages (from-to)35-45
Number of pages11
JournalBlood Cells, Molecules, and Diseases
Volume52
Issue number1
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Chuvash polycythemia
  • Gene expression
  • Hypoxia inducible factor
  • Hypoxia-sensing
  • Iron deficiency
  • VHL

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

Cite this

Zhang, X., Zhang, W., Ma, S. F., Miasniakova, G., Sergueeva, A., Ammosova, T., Xu, M., Nekhai, S., Nourai, M., Wade, M. S., Prchal, J. T., Garcia, J. G. N., Machado, R. F., & Gordeuk, V. R. (2014). Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing. Blood Cells, Molecules, and Diseases, 52(1), 35-45. https://doi.org/10.1016/j.bcmd.2013.07.016