Hemoglobin subunit gamma 1 (HBG1) promoter regulatory adenines (HBG1 promoter adenines)

The Hemoglobin subunit gamma 1 (HBG1) promoter regulatory adenines are specific nucleotide sequences within the promoter region of the gamma-globin gene that play a pivotal role in the fetal-to-adult hemoglobin switch. These adenines are located within binding motifs for key transcriptional repressors, such as BCL11A and ZBTB7A, which actively silence the production of fetal hemoglobin (HbF) in adults (Gaudelli et al., 2017, Nature). In patients with Sickle Cell Disease or Beta-Thalassemia, reactivating HbF is a validated therapeutic strategy to compensate for defective adult beta-globin. Modern gene-editing technologies, specifically adenine base editors (ABEs), target these regulatory adenines to convert them into guanines (Beam Therapeutics, 2024). This conversion mimics naturally occurring mutations found in individuals with Hereditary Persistence of Fetal Hemoglobin (HPFH), effectively preventing repressor binding (Wienert et al., 2018, Nature Communications). By disrupting these silencing signals, the HBG1 promoter is reactivated, leading to high levels of HbF synthesis in erythroid cells (Zeng et al., 2020, Nature Medicine). The primary therapeutic candidate targeting these adenines is BEAM-101, an autologous hematopoietic stem cell therapy currently in clinical trials. This approach offers a precision medicine alternative to traditional gene therapy by making single-nucleotide changes without inducing double-stranded DNA breaks.

Other names

HBG1/HBG2 promoterGamma-globin promoter-175 HPFH site-115 HPFH siteBCL11A binding site in HBG promoter

Disruption of transcriptional repressor binding sites via adenine-to-guanine base editing to induce fetal hemoglobin expression