Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
Science
; 361(6399): 285-290, 2018 07 20.
Article
em En
| MEDLINE
| ID: mdl-30026227
ABSTRACT
Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of ß-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain-focused CRISPR-Cas9-based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hemoglobina Fetal
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Proteínas Nucleares
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Proteínas de Transporte
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Regulação da Expressão Gênica
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EIF-2 Quinase
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Células Eritroides
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Anemia Falciforme
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article