ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin
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
Affiliations
Mandy Y. Boontanrart
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Markus S. Schröder
Department of Biology, ETH Zurich, Zurich 8092, Switzerland
Gautier M. Stehli
Department of Biology, ETH Zurich, Zurich 8092, Switzerland
Marija Banović
Department of Biology, ETH Zurich, Zurich 8092, Switzerland
Stacia K. Wyman
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Rachel J. Lew
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Matteo Bordi
Department of Biology, ETH Zurich, Zurich 8092, Switzerland
Benjamin G. Gowen
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Mark A. DeWitt
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Jacob E. Corn
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Biology, ETH Zurich, Zurich 8092, Switzerland; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Corresponding author
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.
