Competitive binding model offers new view of the fetal-to-adult gene switch
image: Schematic representation of competitive binding between GATA1/NFY and ZBTB7A/BCL11A complexes at the γ-globin promoter. During fetal erythroid maturation, GATA1 and NFY form an activating protein complex that binds the γ-globin promoter. In contrast, ZBTB7A and BCL11A form a repressor complex that mediates the γ-to-β-globin switching process.
Credit: Xin-Ran Wei; Xiao-Hui Huang; Shu-Er Liu; Yu-Jie Zhao; Mei Chen; Di Jin; Yue Gao; Yi-Hui Zhang; Hui-Xin Ai; Yan-Lin Ma; Zheng Liu.
Before birth, the main oxygen-carrying protein in red blood cells is fetal hemoglobin, or HbF, which contains γ-globin. After birth, γ-globin production normally declines and β-globin takes its place, producing adult hemoglobin.
In β-thalassemia, mutations reduce or prevent β-globin production. This leaves excess α-globin chains without partners, damaging developing red blood cells and causing anemia. Reactivating γ-globin offers a way around this problem: γ-globin can pair with α-globin to produce HbF, partially replacing the missing adult hemoglobin.
A new review published in Reproductive and Developmental Medicine examines how proteins binding to the γ-globin promoter may regulate this developmental switch. The authors focus on four transcription factors: GATA1, NFY, BCL11A and ZBTB7A.
Their proposed model can be understood as competition between an activating team and a repressing team. During fetal development, GATA1 and NFY occupy the γ-globin promoter and help keep γ-globin production switched on. Later, levels of the upstream regulator KLF1 rise, increasing the activity of the repressors BCL11A and ZBTB7A.
BCL11A can physically interfere with NFY binding, while ZBTB7A works alongside BCL11A and recruits the NuRD chromatin-remodeling complex. Together, these effects make the promoter less accessible, switch off γ-globin and allow the adult hemoglobin program to predominate. BCL11A and ZBTB7A do not replace the missing β-globin; rather, they normally prevent continued production of its fetal alternative.
The authors describe the GATA1/NFY activating complex and the larger ZBTB7A–NuRD–BCL11A repressive assembly as proposed interactions that still require direct experimental testing.
“This framework offers a refined mechanistic perspective on the pathogenesis of β-thalassemia and highlights promising therapeutic avenues,” the authors write.
The model helps explain why reducing BCL11A activity can benefit people with β-thalassemia. Exagamglogene autotemcel, or exa-cel, edits a red-cell-specific regulatory region of BCL11A, releasing the brake on γ-globin and increasing HbF. It does not repair the defective β-globin gene, but activates an alternative form of hemoglobin.
Future research could test the proposed protein interactions and explore whether γ-globin might also be reactivated by strengthening the GATA1/NFY activating team or preventing its displacement.