Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A

Vijay G. Sankaran, Tobias F. Menne, Jian Xu, Thomas E. Akie, Guillaume Lettre, Ben Van Handel, Hanna K A Mikkola, Joel N. Hirschhorn, Alan B. Cantor, Stuart H. Orkin

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487 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1839-1842
Number of pages4
JournalScience
Volume322
Issue number5909
DOIs
StatePublished - Dec 19 2008

ASJC Scopus subject areas

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    Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., & Orkin, S. H. (2008). Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science, 322(5909), 1839-1842. https://doi.org/10.1126/science.1165409