Hemoglobin subunit gamma 1 and 2 promoter regions (HBG1/2 promoters)

The HBG1 and HBG2 promoter regions are regulatory DNA sequences located upstream of the genes encoding the gamma-globin subunits of fetal hemoglobin (HbF). In normal development, these promoters are silenced shortly after birth during the fetal-to-adult hemoglobin switch, a process mediated by the binding of transcriptional repressors such as BCL11A and ZBTB7A (also known as LRF) to specific motifs within the promoter (Martyn et al., 2018, Nature Genetics). In patients with sickle cell disease or beta-thalassemia, the reactivation of these promoters offers a potent therapeutic strategy to induce HbF, which can substitute for defective adult beta-globin and prevent the polymerization of sickle hemoglobin (Wienert et al., 2018, Nature Communications). Modern gene-editing therapies, such as EDIT-301 and BEAM-101, specifically target these promoter regions to disrupt repressor binding or recreate naturally occurring HPFH mutations (Editas Medicine, 2023; Beam Therapeutics, 2024). By permanently modifying these genomic sites in autologous hematopoietic stem cells, these treatments aim to provide a durable increase in HbF levels, thereby reducing disease symptoms and improving patient outcomes.

Other names

Gamma-globin promotersHBG1 promoterHBG2 promoterA-gamma and G-gamma globin promotersFetal hemoglobin promoters

Disruption of repressor binding sites (such as BCL11A or ZBTB7A/LRF motifs) or introduction of mutations that mimic Hereditary Persistence of Fetal Hemoglobin (HPFH) using CRISPR/Cas9, CRISPR/Cas12a, or base editing to reactivate fetal hemoglobin (HbF) production.