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β-Hemoglobinopathies can trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here, we use CRISPR-Cas genome editing to model the stress caused by reduced levels of adult β-globin. We find that decreased β-globin is sufficient to induce robust re-expression of γ-globin, and RNA sequencing (RNA-seq) of differentiating isogenic erythroid precursors implicates ATF4 as a causal regulator of this response. ATF4 binds within the HBS1L-MYB intergenic enhancer and regulates expression of MYB, a known γ-globin regulator. Overall, the reduction of ATF4 upon β-globin knockout decreases the levels of MYB and BCL11A. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could inform strategies to treat hemoglobinopathies. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.


Mandy Y Boontanrart, Markus S Schröder, Gautier M Stehli, Marija Banović, Stacia K Wyman, Rachel J Lew, Matteo Bordi, Benjamin G Gowen, Mark A DeWitt, Jacob E Corn. ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin. Cell reports. 2020 Aug 04;32(5):107993

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PMID: 32755585

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