Transcription factor competition at the γ-globin promoters controls hemoglobin switching

Nat Genet. 2021 Apr;53(4):511-520. doi: 10.1038/s41588-021-00798-y. Epub 2021 Mar 1.


BCL11A, the major regulator of fetal hemoglobin (HbF, α2γ2) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, α2β2). To uncover how BCL11A initiates repression, we used CRISPR-Cas9, dCas9, dCas9-KRAB and dCas9-VP64 screens to dissect the γ-globin promoters and identified an activator element near the BCL11A-binding site. Using CUT&RUN and base editing, we demonstrate that a proximal CCAAT box is occupied by the activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate repression. Occupancy of NF-Y is rapidly established following BCL11A depletion, and precedes γ-globin derepression and locus control region (LCR)-globin loop formation. Our findings reveal that the switch from fetal to adult globin gene expression within the >50-kb β-globin gene cluster is initiated by competition between a stage-selective repressor and a ubiquitous activating factor within a remarkably discrete region of the γ-globin promoters.

Publication types

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

MeSH terms

  • Base Sequence
  • Binding Sites
  • Binding, Competitive
  • CCAAT-Binding Factor / chemistry*
  • CCAAT-Binding Factor / genetics
  • CCAAT-Binding Factor / metabolism
  • Erythropoiesis / genetics
  • Fetal Hemoglobin / genetics*
  • Fetal Hemoglobin / metabolism
  • Gene Editing / methods
  • Gene Expression Regulation
  • HEK293 Cells
  • Hemoglobin A / genetics*
  • Hemoglobin A / metabolism
  • Humans
  • Models, Molecular
  • Primary Cell Culture
  • Promoter Regions, Genetic*
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Stem Cells
  • beta-Globins / chemistry
  • beta-Globins / genetics
  • beta-Globins / metabolism
  • gamma-Globins / chemistry*
  • gamma-Globins / genetics
  • gamma-Globins / metabolism


  • BCL11A protein, human
  • CCAAT-Binding Factor
  • Repressor Proteins
  • beta-Globins
  • gamma-Globins
  • Hemoglobin A
  • Fetal Hemoglobin