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Blood Cells Mol Dis. 2014 Jan;52(1):35-45. doi: 10.1016/j.bcmd.2013.07.016. Epub 2013 Aug 28.

Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing.

Author information

1
Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
2
Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA.
3
Institute of Human Genetics, University of Illinois at Chicago, Chicago, IL, USA.
4
Section of Pulmonary/Critical Care, Department of Medicine, University of Chicago, Chicago, IL, USA.
5
Chuvash Republic Clinical Hospital 2, Cheboksary, Russian Federation, Howard University, Washington, DC.
6
Cheboksary Children's Hospital, Cheboksary, Russian Federation, Howard University, Washington, DC.
7
Center for Sickle Cell Disease, Howard University, Washington, DC.
8
Section of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
9
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
10
Departments of Medicine, Pathology and Genetics, University of Utah and VAH.
#
Contributed equally

Abstract

In congenital Chuvash polycythemia (CP), VHL(R200W) 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 VHL(R200W) 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 VHL(R200W) homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHL(R200W) 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.

KEYWORDS:

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

PMID:
23993337
PMCID:
PMC3852195
DOI:
10.1016/j.bcmd.2013.07.016
[Indexed for MEDLINE]
Free PMC Article

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