Hemoglobin subunit gamma 1 and 2 promoters (HBG1/HBG2 promoters)

The HBG1/HBG2 promoters, specifically the region around the -110 base pair (bp) site, serve as a critical regulatory hub for the expression of fetal hemoglobin (HbF). In normal development, this region is targeted by repressor proteins such as BCL11A and ZBTB7A (also known as LRF) to silence the gamma-globin genes during the transition from fetal to adult erythropoiesis (Martyn et al., 2018; Masuda et al., 2016). Mutations in this "hereditary persistence of fetal hemoglobin (HPFH)-like site" disrupt the binding of these repressors, leading to the continued production of HbF into adulthood. This site has become a primary target for genomic therapies aimed at treating hemoglobinopathies like sickle cell disease and beta-thalassemia. By using gene-editing tools like CRISPR/Cas12a or base editors to modify this promoter region, clinicians can mimic the HPFH phenotype, thereby reactivating HbF production to compensate for defective adult hemoglobin (Editas Medicine, 2023; Beam Therapeutics, 2023). This approach provides a durable, potentially curative treatment by leveraging the body's own regulatory mechanisms to restore functional hemoglobin levels.

Other names

HBG1/HBG2 -110 siteGamma-globin promoterHPFH-like siteDistal CCAAT box region

Disruption of transcription factor binding sites (e.g., BCL11A or ZBTB7A) within the HBG1/HBG2 promoters to prevent repression and induce fetal hemoglobin (HbF) synthesis.