Globin gene cluster

The globin gene cluster and its associated regulatory factors, collectively known as genes involved in hemoglobin production, encompass the alpha-globin (HBA1, HBA2) and beta-globin (HBB, HBG1, HBG2) loci on chromosomes 16 and 11, respectively [5, 10, 13]. These genes provide instructions for synthesizing the subunits of the hemoglobin tetramer, the essential oxygen-carrying protein in red blood cells. A critical regulatory component of this system is the BCL11A transcription factor, which acts as a molecular switch to repress fetal hemoglobin (HbF) in favor of adult hemoglobin (HbA) shortly after birth [1, 2, 4]. Mutations in these genes, particularly within the HBB locus, are the primary cause of hereditary hemoglobinopathies like sickle cell disease and beta-thalassemia, which lead to chronic anemia and organ damage due to hemolysis and vaso-occlusion [18, 19, 20]. Modern therapeutic strategies focus on manipulating these genes to restore functional oxygen delivery, either by inserting corrected copies of the beta-globin gene or by utilizing gene editing to disable BCL11A and reactivate protective levels of fetal hemoglobin [2, 7, 12, 15].

Other names

Genes involved in hemoglobin productionHemoglobin genesHBBHBAHBGBCL11A (regulatory factor)Hemoglobin subunit

Drugs targeting these genes or their products act through several mechanisms: ex vivo CRISPR/Cas9-mediated disruption of the BCL11A erythroid-specific enhancer to reactivate fetal hemoglobin (HbF) production [2, 6]; lentiviral-mediated addition of functional beta-globin (HBB) genes into hematopoietic stem cells [12]; and small molecule stabilization of hemoglobin in the oxygenated state to inhibit sickle hemoglobin polymerization [8].