| Literature DB >> 30026227 |
Jeremy D Grevet1,2, Xianjiang Lan1, Nicole Hamagami1, Christopher R Edwards1, Laavanya Sankaranarayanan1, Xinjun Ji2, Saurabh K Bhardwaj1, Carolyne J Face1, David F Posocco1, Osheiza Abdulmalik1, Cheryl A Keller3, Belinda Giardine3, Simone Sidoli4, Ben A Garcia4, Stella T Chou1, Stephen A Liebhaber2, Ross C Hardison3, Junwei Shi5, Gerd A Blobel6,2.
Abstract
Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of β-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.Entities:
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Year: 2018 PMID： 30026227 PMCID： PMC6257981 DOI： 10.1126/science.aao0932
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728