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

doi:10.1126/science.aao0932

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

Research output: Contribution to journal › Article › peer-review

103 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 language	English (US)
Pages (from-to)	285-290
Number of pages	6
Journal	Science
Volume	361
Issue number	6399
DOIs	https://doi.org/10.1126/science.aao0932
State	Published - Jul 20 2018
Externally published	Yes

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General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.aao0932

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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

Grevet, JD, Lan, X, Hamagami, N, Edwards, CR, Sankaranarayanan, L, Ji, X, Bhardwaj, SK, Face, CJ, Posocco, DF, Abdulmalik, O, Keller, CA, Giardine, B, Sidoli, S, Garcia, BA, Chou, ST, Liebhaber, SA, Hardison, RC, Shi, J & Blobel, GA 2018, 'Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells', Science, vol. 361, no. 6399, pp. 285-290. https://doi.org/10.1126/science.aao0932

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

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.",

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

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doi = "10.1126/science.aao0932",

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AU - Grevet, Jeremy D.

AU - Lan, Xianjiang

AU - Hamagami, Nicole

AU - Edwards, Christopher R.

AU - Sankaranarayanan, Laavanya

AU - Ji, Xinjun

AU - Bhardwaj, Saurabh K.

AU - Face, Carolyne J.

AU - Posocco, David F.

AU - Abdulmalik, Osheiza

AU - Keller, Cheryl A.

AU - Giardine, Belinda

AU - Sidoli, Simone

AU - Garcia, Ben A.

AU - Chou, Stella T.

AU - Liebhaber, Stephen A.

AU - Hardison, Ross C.

AU - Shi, Junwei

AU - Blobel, Gerd A.

PY - 2018/7/20

Y1 - 2018/7/20

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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