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 language | English (US) |
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Pages (from-to) | 35-45 |
Number of pages | 11 |
Journal | Blood Cells, Molecules, and Diseases |
Volume | 52 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2014 |
Funding
This work was supported in part by R01 HL079912-04 (VRG) from the National Heart, Lung and Blood Institute (NHLBI) , 2 R25-HL03679-08 (VRG) from the NHLBI and the Office of Research on Minority Health, Howard University General Clinical Research Grant Nos. MO1-PR10284 , K23HL098454 (RFM), SC1GM082325 (SN), 2G12RR003048 (SN), 8G12MD007597 (SN), and 1P30HL107253 (VRG and SN). RFM is supported by NIH R01HL111656 . JTP is supported by NIH- P01CA108671 and VAH and thus his material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Clinical Sciences Research and Development including the Cooperative Studies Program, Rehabilitation Research and Development Service, and Health Services Research and Development.
Keywords
- Chuvash polycythemia
- Gene expression
- Hypoxia inducible factor
- Hypoxia-sensing
- Iron deficiency
- VHL
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Hematology
- Cell Biology