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

TitleIron deficiency modifies gene expression variation induced by augmented hypoxia sensing.
Publication TypeJournal Article
Year of Publication2014
AuthorsZhang X, Zhang W, Ma S-F, Miasniakova G, Sergueeva A, Ammosova T, Xu M, Nekhai S, Nourai M, Wade MS, Prchal JT, Garcia JGN, Machado RF, Gordeuk VR
JournalBlood Cells Mol Dis
Volume52
Issue1
Pagination35-45
Date Published2014 Jan
ISSN Number1096-0961
KeywordsAnemia, Iron-Deficiency, Basic Helix-Loop-Helix Transcription Factors, Blood Glucose, Gene Expression Regulation, Homozygote, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Innate, Insulin, Iron, Leukocytes, Mononuclear, Phlebotomy, Polycythemia, Protein Stability, Signal Transduction, Von Hippel-Lindau Tumor Suppressor Protein
Abstract

<p>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.</p>

DOI10.1016/j.bcmd.2013.07.016
Alternate JournalBlood Cells Mol. Dis.
PubMed ID23993337
PubMed Central IDPMC3852195
Grant ListR01 HL079912-04 / HL / NHLBI NIH HHS / United States
P01CA108671 / CA / NCI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States
SC1 GM082325 / GM / NIGMS NIH HHS / United States
R01 HL125005 / HL / NHLBI NIH HHS / United States
G12 MD007597 / MD / NIMHD NIH HHS / United States
G12 RR003048 / RR / NCRR NIH HHS / United States
K23 HL098454 / HL / NHLBI NIH HHS / United States
P30 HL107253 / HL / NHLBI NIH HHS / United States
P50 HL118006 / HL / NHLBI NIH HHS / United States
P01 CA108671 / CA / NCI NIH HHS / United States
8G12MD007597 / MD / NIMHD NIH HHS / United States
MO1-PR10284 / PR / OCPHP CDC HHS / United States
1P30HL107253 / HL / NHLBI NIH HHS / United States
R25 HL003679 / HL / NHLBI NIH HHS / United States
R01 HL079912 / HL / NHLBI NIH HHS / United States
R01HL111656 / HL / NHLBI NIH HHS / United States
2 R25-HL03679-08 / HL / NHLBI NIH HHS / United States
SC1GM082325 / GM / NIGMS NIH HHS / United States
M01 RR010284 / RR / NCRR NIH HHS / United States
K23HL098454 / HL / NHLBI NIH HHS / United States
UH1 HL003679 / HL / NHLBI NIH HHS / United States
2G12RR003048 / RR / NCRR NIH HHS / United States