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

Cell Rep. 2020 Aug 4;32(5):107993. doi: 10.1016/j.celrep.2020.107993.


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.

Keywords: BCL11A; CRISPR/Cas9; Fetal hemoglobin; HBS1L-MYB; adult hemoglobin; gene editing; hemoglobinopathies; stress erythropoiesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Base Sequence
  • Cell Differentiation / genetics
  • Cell Line
  • DNA, Intergenic / genetics
  • Down-Regulation / genetics
  • Enhancer Elements, Genetic / genetics
  • Fetal Hemoglobin / genetics
  • Gene Expression Regulation*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Mutation / genetics
  • Protein Binding
  • Proto-Oncogene Proteins c-myb / genetics*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Repressor Proteins / metabolism
  • Time Factors
  • Transcription, Genetic
  • Transcriptome / genetics
  • Up-Regulation / genetics
  • beta-Globins / metabolism*
  • gamma-Globins / genetics*
  • gamma-Globins / metabolism


  • BCL11A protein, human
  • DNA, Intergenic
  • MYB protein, human
  • Proto-Oncogene Proteins c-myb
  • Repressor Proteins
  • beta-Globins
  • gamma-Globins
  • Activating Transcription Factor 4
  • Fetal Hemoglobin