Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A

Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high- HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full- length forms of BCL11A is developmentally restricted to adult erythroid cells. Down- regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta- globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta- hemoglobin disorders.