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

VG Sankaran, TF Menne, J Xu, TE Akie, G Lettre… - Science, 2008 - science.org
Science, 2008science.org
Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the
severity of sickle cell disease and the β-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 …
Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-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 β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.
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