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DOI | 10.1126/science.aao0932 |
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells | |
Grevet, Jeremy D.1,2; Lan, Xianjiang1; Hamagami, Nicole1; Edwards, Christopher R.1; Sankaranarayanan, Laavanya1; Ji, Xinjun2; Bhardwaj, Saurabh K.1; Face, Carolyne J.1; Posocco, David F.1; Abdulmalik, Osheiza1; Keller, Cheryl A.3; Giardine, Belinda3; Sidoli, Simone4; Garcia, Ben A.4; Chou, Stella T.1; Liebhaber, Stephen A.2; Hardison, Ross C.3; Shi, Junwei5; Blobel, Gerd A.1,2 | |
2018-07-20 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 361期号:6399页码:285-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000439145800045 |
WOS关键词 | EIF2-ALPHA KINASE ; IRON-DEFICIENCY ; BCL11A ; EXPRESSION ; PRECURSORS ; INDUCTION ; MORTALITY ; ENHANCER ; DISEASE ; MICE |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/199203 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA; 2.Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA; 3.Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA; 4.Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA; 5.Univ Penn, Dept Canc Biol, Perelman Sch Med, Philadelphia, PA 19104 USA |
推荐引用方式 GB/T 7714 | Grevet, Jeremy D.,Lan, Xianjiang,Hamagami, Nicole,et al. Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells[J]. SCIENCE,2018,361(6399):285-+. |
APA | Grevet, Jeremy D..,Lan, Xianjiang.,Hamagami, Nicole.,Edwards, Christopher R..,Sankaranarayanan, Laavanya.,...&Blobel, Gerd A..(2018).Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.SCIENCE,361(6399),285-+. |
MLA | Grevet, Jeremy D.,et al."Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells".SCIENCE 361.6399(2018):285-+. |
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