Molecular regulation of the fetal-to-adult hemoglobin switch. The human β-globin gene locus, which is located on chromosome 11, has a series of 5 genes that are developmentally expressed at distinct stages of human ontogeny (panel A bottom). The ε-globin gene is restricted to the transiently expressed embryonic primitive lineage of RBC produced in the first several weeks of gestation. The γ-globin genes encode the genes that uniquely form HbF, which is the predominant hemoglobin during the course of gestation. There is a switch to expression of the adult β-globin gene around the time of birth (B). B-cell lymphoma/leukemia 11A (BCL11A) and its protein partners, including GATA binding protein 1 (GATA1), zinc finger protein multi-type 1 (ZFPM1 or FOG1), and the nucleosome remodeling and deacetylase (NuRD) complex, bind to sequences within the globin locus (panel A tan ovals) and repress the expression of the γ-globin genes. Krüppel-like factor 1 (KLF1) interacts with this process by positively regulating the expression of BCL11A (green arrow in panel A) and also by directly binding to and promoting transcription of the adult β-globin gene. It is unknown whether KLF1 affects HbF expression through more global effects on erythropoiesis (panel A top), which may also be targeted by other factors associated with HbF (eg, MYB). HSs indicates DNase I–hypersensitive sites; LCR, locus control region. (Reprinted with permission from Sankaran and Nathan.⁷ )