Transcription factor binding to the γ-globin promoter regulates the γ-to-β-globin switch

Patients with severe β-thalassemia face not only lifelong dependence on blood transfusions but also the management of serious and potentially life-threatening complications. The pathophysiology of this disorder is largely attributed to a defective transition from γ-globin to β-globin gene expression, a process essential for normal hemoglobin production after birth. This developmental transition involves the silencing of fetal γ-globin and coordinated activation of adult β-globin gene transcription. Central to this regulation are transcription factors that directly bind to the γ-globin promoter. This review synthesizes recent advances in understanding the γ-to-β-globin switch, focusing on four principal transcription factors—GATA1, BCL11A, ZBTB7A, and NFY—and partner proteins including GATA2 and KLF1. In addition, we propose a competitive binding model in which the GATA1/NFY and ZBTB7A/BCL11A protein complexes compete for promoter occupancy. This model provides a useful framework that may inform future strategies for the prevention, diagnosis, and treatment of β-thalassemia.