ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin

Cell Reports

卷:32

Rachel J. Lew¹  Marija Banović²  Markus S. Schröder²  Gautier M. Stehli²  Benjamin G. Gowen²  Stacia K. Wyman³  Mandy Y. Boontanrart³  Mark A. DeWitt³  Matteo Bordi³  Jacob E. Corn³ 

[1] Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA;

[2] Department of Biology, ETH Zurich, Zurich 8092, Switzerland;

[3] Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA;

关键词: Fetal hemoglobin;    adult hemoglobin;    stress erythropoiesis;    BCL11A;    HBS1L-MYB;    hemoglobinopathies;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown