Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities

Abstract

In humans, embryonic, fetal, and adult hemoglobins are sequentially expressed in developing erythroblasts during ontogeny. For the past 40 years, this process has been the subject of intensive study because of its value to enlighten the biology of developmental gene regulation and because fetal hemoglobin can significantly ameliorate the clinical manifestations of both sickle cell disease and β-thalassemia. Understanding the normal process of loss of fetal globin expression and activation of adult globin expression could potentially lead to new therapeutic approaches for these hemoglobin disorders. Herein, we briefly review the history of the study of hemoglobin switching and then focus on recent discoveries in the field that now make new therapeutic approaches seem feasible in the future. Erythroid-specific knockdown of fetal gene repressors or enforced expression of fetal gene activators may provide clinically applicable approaches for genetic treatment of hemoglobin disorders that would benefit from increased fetal hemoglobin levels.

Figure 1

Schematic of genomic structural organization of the human α-globin and β-globin loci and temporal expression of the various hemoglobin types. The gene order of the α-globin locus on chromosome 16 and the β-globin locus on chromosome 11. Shown at each temporal stage, as indicated on the timeline at bottom, are the types of hemoglobin tetramers produced for each indicated site. LCR indicates locus control region; HbF, fetal hemoglobin; and HbA, adult hemoglobin.

Figure 2

Schematic of hemoglobin switching model based on looping and interaction of the LCR with the individual globin gene promoters. The various proteins demonstrated experimentally to be involved in regulating the change in expression from γ-globin to β-globin and individual effects of FOP and KLF1 on transcriptional regulation of SOX6 and BCL11A, respectively.