Hemoglobin subunit gamma 1 and 2 promoter and enhancer DNA elements (HBG promoter/enhancer)

The Hemoglobin subunit gamma 1 and 2 (HBG1/HBG2) promoter and enhancer DNA elements are non-coding regulatory sequences that control the expression of fetal hemoglobin (HbF). During the perinatal period, these elements undergo a developmental switch where they are silenced by the binding of repressor proteins like BCL11A and ZBTB7A (LRF), leading to the transition from fetal to adult hemoglobin (NIH, 2023). In patients with sickle cell disease and beta-thalassemia, these DNA elements serve as primary therapeutic targets for gene editing. By using CRISPR-Cas9 or base editing technologies to disrupt the repressor binding sites within the HBG promoters, researchers can mimic the phenotype of Hereditary Persistence of Fetal Hemoglobin (HPFH), effectively restarting HbF production (Wienert et al., 2018). This induction of HbF compensates for the lack of functional adult beta-globin, preventing the polymerization of sickle hemoglobin and reducing clinical complications (Editas Medicine, 2024). Current clinical candidates targeting these specific DNA sequences include EDIT-301 and BEAM-101, which aim to provide a one-time curative treatment for hemoglobinopathies (Beam Therapeutics, 2024).

Other names

HBG1/HBG2 promoterGamma-globin promoterFetal hemoglobin regulatory elementsHbF promoter

Targeted disruption of repressor binding motifs (e.g., the distal CCAAT box or BCL11A binding sites) within the HBG1 and HBG2 promoters using gene editing tools to derepress gamma-globin expression and increase fetal hemoglobin levels.