BCL11A-binding site at -110 in the Hemoglobin subunit gamma-2 promoter (HBG2 -110 BCL11A site)

The BCL11A-binding site at -110 (more precisely centered at -115 bp) in the Hemoglobin subunit gamma-2 (HBG2) promoter is a critical DNA regulatory element that controls the silencing of fetal hemoglobin (HbF) after birth (Martyn et al., 2018, Nature Genetics). This site contains a highly conserved TGACCA motif where the zinc-finger transcription factor BCL11A binds directly to recruit co-repressor complexes, such as NuRD, effectively shutting down the expression of the gamma-globin genes in adult erythroid cells (Liu et al., 2018, Nature Genetics). Naturally occurring mutations in this specific region are associated with Hereditary Persistence of Fetal Hemoglobin (HPFH), a condition where individuals continue to produce high levels of HbF throughout life, which significantly alleviates the symptoms of Sickle Cell Disease and Beta-Thalassemia (Wienert et al., 2018, Nature Communications). Consequently, this site has emerged as a primary therapeutic target for gene editing. Therapeutic candidates like EDIT-301 (Edralbragene autotemcel) utilize CRISPR/Cas12a to specifically disrupt this binding motif in hematopoietic stem cells, thereby mimicking the HPFH phenotype and re-activating HbF production to provide functional oxygen transport (Editas Medicine, 2023; Vinh et al., 2022, Blood).

Other names

HBG2 -115 BCL11A binding siteDistal CCAAT box BCL11A motifHBG2 -114/-115 siteFetal hemoglobin repressor binding siteGamma-globin promoter BCL11A motif

Disruption of the BCL11A repressor binding site via gene editing to induce fetal hemoglobin (HbF) expression.