New paper by the Corn lab on "ATF4 regulates MYB to increase gamma-globin in response to loss of beta-globin" published in Cell Reports.
- Loss of beta-globin leads to upregulation of gamma-globin via altered ATF4 signaling
- Reduced ATF4 decreases the levels of MYB and BCL11A
- ATF4 induces MYB through binding at the HBS1L-MYB intergenic enhancer
Beta-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 gamma-globin. However, the mechanisms underlying gamma-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 beta-globin. We find that decreased beta-globin is sufficient to induce robust re-expression of gamma-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 gamma-globin regulator. Overall, the reduction of ATF4 upon beta-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.