title: Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism.
abstract: Strategies to increase fetal hemoglobin (HbF) levels can ameliorate symptoms and improve the lives of β-hemoglobinopathy patients. Although most studies have focused on induction of γ-globin gene expression as an approach to induce HbF, we hypothesized that post-transcriptional regulation of HbF plays an underappreciated yet important role in controlling HbF levels. In the present study, we investigated whether increasing eukaryotic initiation factor 2α (eIF2α) phosphorylation, a key regulator of protein translation, could enhance HbF post-transcriptionally in human primary erythroid cells. Initial analysis using a known inhibitor of eIF2α dephosphorylation, salubrinal, revealed that elevated eIF2α phosphorylation enhanced HbF production without changing globin gene expression, proliferation, or cell differentiation. These results were further supported by the post-transcriptional induction of HbF by other pharmacologic activators of the eIF2α pathway and by genetic inactivation of the negative regulators, GADD34 and CReP. Additionally, we found that this novel mechanism of increasing HbF could be combined with clinically relevant transcriptional activators of γ-globin gene expression to additively enhance HbF. Taken together, these findings identify eIF2α phosphorylation as a post-transcriptional regulator of HbF induction that may be pharmacologically targeted, either alone or in combination, in β-hemoglobinopathy patients.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Hahn
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lowrey
mesh_terms: D002934:Cinnamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism* / Q000502:physiology; D005319:Fetal Hemoglobin / Q000378:metabolism*; D006453:Hemoglobinopathies / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D020014:K562 Cells; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D010766:Phosphorylation / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D002934:Cinnamates; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D005319:Fetal Hemoglobin; D013890:Thiourea