Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells

Jeremy D. Grevet, Xianjiang Lan, Nicole Hamagami, Christopher R. Edwards, Laavanya Sankaranarayanan, Xinjun Ji, Saurabh K. Bhardwaj, Carolyne J. Face, David F. Posocco, Osheiza Abdulmalik, Cheryl A. Keller, Belinda Giardine, Simone Sidoli, Ben A. Garcia, Stella T. Chou, Stephen A. Liebhaber, Ross C. Hardison, Junwei Shi, Gerd A. Blobel

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18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)285-290
Number of pages6
JournalScience
Volume361
Issue number6399
DOIs
StatePublished - Jul 20 2018
Externally publishedYes

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Cite this

Grevet, J. D., Lan, X., Hamagami, N., Edwards, C. R., Sankaranarayanan, L., Ji, X., Bhardwaj, S. K., Face, C. J., Posocco, D. F., Abdulmalik, O., Keller, C. A., Giardine, B., Sidoli, S., Garcia, B. A., Chou, S. T., Liebhaber, S. A., Hardison, R. C., Shi, J., & Blobel, G. A. (2018). Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science, 361(6399), 285-290. https://doi.org/10.1126/science.aao0932