Interplay between KLF1 and BCL11a in the regulation of hemoglobin switching. (A) During normal development, KLF1 activates transcription of the BCL11A gene, which in turn represses γ globin expression promoting the switch from fetal (α2γ2) to adult (α2β2) hemoglobin. Simultaneously, high levels of KLF1 activate β-globin gene expression. (B) In some cases of HPFH, haplo-insufficiency of KLF1 (KLF1*) is associated with reduced BCL11A expression, which allows for persistence of fetal hemoglobin. Simultaneously, reduced KLF1 fails to activate β-globin expression.