title: Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing.
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.
authors.affiliation: Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA.|Institute of Human Genetics, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Section of Pulmonary/Critical Care, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.affiliation: Chuvash Republic Clinical Hospital 2, Cheboksary, Russian Federation, Howard University, Washington, DC.
authors.forename: Galina
authors.initials: G
authors.lastname: Miasniakova
authors.affiliation: Cheboksary Children's Hospital, Cheboksary, Russian Federation, Howard University, Washington, DC.
authors.forename: Adelina
authors.initials: A
authors.lastname: Sergueeva
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ammosova
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
authors.affiliation: Center for Sickle Cell Disease, Howard University, Washington, DC.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nourai
authors.affiliation: Section of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.|Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wade
authors.affiliation: Departments of Medicine, Pathology and Genetics, University of Utah and VAH.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.affiliation: Section of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.|Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Joe G N
authors.initials: JGN
authors.lastname: Garcia
authors.affiliation: Section of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.|Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.affiliation: Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate; D007328:Insulin / Q000097:blood; D007501:Iron / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D018962:Phlebotomy / Q000009:adverse effects; D011086:Polycythemia / Q000151:congenital* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D007501:Iron; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human
keywords: Chuvash polycythemia; Gene expression; Hypoxia inducible factor; Hypoxia-sensing; Iron deficiency; VHL