Journal
SCIENCE
Volume 361, Issue 6399, Pages 285-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aao0932
Keywords
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Funding
- Cold Spring Harbor Laboratory
- [T32GM008216]
- [1F30DK107055-01]
- [W81XWH-113-1-0426]
- [R01-GM110174]
- [R01-AI118891]
- [R56DK065806]
- [U54HG006998]
- [R01-HL065449]
- [5R01HL119479]
- [5R37DK058044]
- NATIONAL CANCER INSTITUTE [P30CA016520] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL119479, R01HL065449] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG006998] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI118891] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R24DK106766, F30DK107055, R37DK058044, R01DK054937, R56DK065806] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008216, R01GM110174] Funding Source: NIH RePORTER
- National Institute on Minority Health and Health Disparities [R01MD009124] Funding Source: NIH RePORTER
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Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta-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.
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