Gamma-globin gene expression pathway (HbF induction pathway) (HbF induction)

The gamma-globin gene expression pathway regulates the production of gamma-globin chains (HBG1 and HBG2), which are essential components of fetal hemoglobin (HbF; alpha2gamma2). In humans, this pathway is naturally silenced shortly after birth through a process known as hemoglobin switching, where adult beta-globin (HBB) replaces gamma-globin (Sankaran & Orkin, 2013). This silencing is primarily controlled by transcriptional repressors such as BCL11A and ZBTB7A (LRF), which recruit epigenetic modifiers like histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) to the HBG promoters to induce a repressive chromatin state (Bauer et al., 2013). Reactivating this pathway is a critical therapeutic goal for treating beta-hemoglobinopathies like sickle cell disease and beta-thalassemia, as elevated HbF can functionally compensate for defective or absent adult hemoglobin and inhibit the polymerization of sickle hemoglobin (Lettre & Bauer, 2016). Pharmacological agents like hydroxyurea and decitabine induce gamma-globin expression by stimulating stress erythropoiesis or inhibiting DNA methylation, respectively (Saunthararajah, 2013). Advanced gene therapies, such as exagamglogene autotemcel, target the erythroid-specific enhancer of BCL11A to permanently reactivate gamma-globin production in hematopoietic stem cells (Frangoul et al., 2021). Monitoring HbF levels and F-cell counts serves as a primary biomarker for the efficacy of these treatments, while safety concerns include myelosuppression from cytotoxic agents and potential off-target effects from genomic editing.

Other names

Fetal hemoglobin induction pathwayHBG1/HBG2 expression pathwayHemoglobin switching pathwayGamma-globin induction

Reactivation of fetal hemoglobin (HbF) synthesis by inhibiting transcriptional repressors (e.g., BCL11A, ZBTB7A) or modifying chromatin structure at the HBG1/HBG2 promoters via HDAC or DNMT inhibition.