biostudies-literatureMyers GU.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical SciencesNIDDK NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIAID NIH HHSU.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious DiseasesNHLBI NIH HHSU.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood InstituteU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)NCI NIH HHSNIGMS NIH HHSU.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases3488https://www.ebi.ac.uk/biostudies/studies/S-EPMC11993733biostudies-literatureUnknown16(1)The complete array of genes required for terminal erythroid differentiation remains unknown. To address this knowledge gap, we perform a genome-scale CRISPR knock-out screen in the human erythroid progenitor cell line HUDEP-2 and validate candidate regulators of erythroid differentiation in a custom secondary screen. Comparison of sgRNA abundance in the CRISPR library, proerythroblasts, and orthochromatic erythroblasts, resulted in the identification of genes that are essential for proerythroblast survival and genes that are required for terminal erythroid differentiation. Among the top genes identified are known regulators of erythropoiesis, underscoring the validity of this screen. Notably, using a Log2 fold change of <-1 and false discovery rate of <0.01, the screen identified 277 genesNature communicationsA genome-wide screen identifies genes required for erythroid differentiation.PMC11993733U01 HL117658P30 CA008748T32 GM007863R01 HL148333T32 GM007315P01 HL146372AI091627R01 AI091627T32-GM007315F31 HL162544K08 DK127013U54 DK106829U2C DK129445TL1 DK136046R01 HL157062Yu LLin ZFriedman ALiu XMcGee BBalbin-Cuesta GIto MAKurita RBergin ILKhoriaty RWang YTang VSiemieniak DLim KCWeisman LSKerpet CDrysdale CKu CJOzel ABSingh SAPourmandi NNakamura YEngel JDSaba RLyssiotis CAMyers GJohnson CNMaillard IfalseA genome-wide screen identifies genes required for erythroid differentiation.The complete array of genes required for terminal erythroid differentiation remains unknown. To address this knowledge gap, we perform a genome-scale CRISPR knock-out screen in the human erythroid progenitor cell line HUDEP-2 and validate candidate regulators of erythroid differentiation in a custom secondary screen. Comparison of sgRNA abundance in the CRISPR library, proerythroblasts, and orthochromatic erythroblasts, resulted in the identification of genes that are essential for proerythroblast survival and genes that are required for terminal erythroid differentiation. Among the top genes identified are known regulators of erythropoiesis, underscoring the validity of this screen. Notably, using a Log2 fold change of <-1 and false discovery rate of <0.01, the screen identified 277 genes2025-01-01T00:00:00Z2025 Apr2026-07-15T11:07:29.468Z2025-07-05T03:04:40.51ZS-EPMC119937334022146010.1038/s41467-025-58739-w