A genome-wide screen identifies genes required for erythroid differentiation Journal Article
| Authors: | Myers, G.; Friedman, A.; Yu, L.; Pourmandi, N.; Kerpet, C.; Ito, M. A.; Saba, R.; Tang, V.; Ozel, A. B.; Bergin, I. L.; Johnson, C. N.; Ku, C. J.; Wang, Y.; Balbin-Cuesta, G.; Lim, K. C.; Lin, Z.; Drysdale, C.; McGee, B.; Kurita, R.; Nakamura, Y.; Liu, X.; Siemieniak, D.; Singh, S. A.; Lyssiotis, C. A.; Maillard, I.; Weisman, L. S.; Engel, J. D.; Khoriaty, R. |
| Article Title: | A genome-wide screen identifies genes required for erythroid differentiation |
| Abstract: | 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 genes that are required for terminal erythroid differentiation, including multiple genes not previously nominated through GWAS. NHLRC2, which was previously implicated in hemolytic anemia, was a highly ranked gene. We suggest that anemia due to NHLRC2 mutation results at least in part from a defect in erythroid differentiation. Another highly ranked gene in the screen is VAC14, which we validated for its requirement in erythropoiesis in vitro and in vivo. Thus, data from this CRISPR screen may help classify the underlying mechanisms that contribute to erythroid disorders. © The Author(s) 2025. |
| Keywords: | survival; controlled study; unclassified drug; human cell; gene deletion; genetics; mutation; nonhuman; mouse; animal; cytology; metabolism; animals; mice; animal tissue; gene targeting; apoptosis; anemia; bone marrow; erythroblast; erythroid precursor cell; erythropoiesis; spleen; erythroid precursor cells; cell line; genome-wide association study; hemoglobin blood level; in vivo study; cell differentiation; in vitro study; messenger rna; gene identification; erythroid cell; hemolytic anemia; genome; mean corpuscular volume; down regulation; erythroblasts; hydrocortisone; protein kinase; short hairpin rna; spleen weight; differentiation; transcription factor gata 1; erythroid cells; erythrocyte count; gene knockout techniques; false discovery rate; array; interleukin 3; puromycin; alpha4 integrin; fetus liver; fluorescence intensity; humans; human; article; clustered regularly interspaced short palindromic repeat; crispr cas system; crispr-cas systems; crispr-cas9 system; hek293t cell line; gene knockout; congenital dyserythropoietic anemia; cd233 antigen; alas2 gene; epor gene; hmbs gene; klf1 gene; nhlrc2 gene; urod gene; vac14 gene |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-04-12 |
| Start Page: | 3488 |
| Language: | English |
| DOI: | 10.1038/s41467-025-58739-w |
| PUBMED: | 40221460 |
| PROVIDER: | scopus |
| PMCID: | PMC11993733 |
| DOI/URL: | |
| Notes: | Source: Scopus |
