Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
复制标题
DOI：
10.1126/science.aao0932
复制
发表时间：
2018-07-20
期刊：
影响因子：
--
通讯作者：
Blobel GA
中科院分区：
文献类型：
--
作者：
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
成人红细胞中胎儿血红蛋白（HbF）水平的增加为镰状细胞病和某些形式的β-地中海贫血患者提供了临床益处。为了在成人红细胞中鉴定潜在的可药物化HbF调节剂，我们采用了一种基于蛋白激酶结构域的CRISPR-Cas9基因筛选，该基因筛选具有新优化的单向导RNA支架。筛选发现血红素调节抑制剂HRI（也称为EIF 2AK 1），一种控制蛋白质翻译的红细胞特异性激酶，作为HbF阻遏物。在培养的红系细胞中，HRI耗竭以特定方式显著增加HbF产生并减少镰状化。HbF阻遏物BCL 11 A的表达减少在很大程度上解释了HRI耗竭的影响。总之，这些结果表明HRI作为血红蛋白病的潜在治疗靶点。
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.
登录
查看更多内容
影响因子：
3.7
作者：
Kurita R;Suda N;Sudo K;Miharada K;Hiroyama T;Miyoshi H;Tani K;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
20.3
作者：
Hahn, Cynthia K.;Lowrey, Christopher H.
通讯作者：
Lowrey, Christopher H.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
158.5
作者：
PLATT, OS;BRAMBILLA, DJ;KLUG, PP
通讯作者：
KLUG, PP
影响因子：
20.3
作者：
Bakanay, SM;Dainer, E;Kutlar, A
通讯作者：
Kutlar, A