Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch

Fetal hemoglobin (HbF, α₂γ₂) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α₂β₂) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. The developmental transition between fetal and adult hemoglobin is controlled by a repressor that acts directly at the γ-globin gene promoter, suggesting a simplified control mechanism that could be manipulated in treatment of γ-hemoglobin disorders.