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Originally published in Science Express on 4 December 2008
Science 19 December 2008:
Vol. 322. no. 5909, pp. 1839 - 1842
DOI: 10.1126/science.1165409
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Reports

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

Vijay G. Sankaran,1,2 Tobias F. Menne,1 Jian Xu,1 Thomas E. Akie,1 Guillaume Lettre,3,4 Ben Van Handel,5 Hanna K. A. Mikkola,5 Joel N. Hirschhorn,3,4 Alan B. Cantor,1 Stuart H. Orkin1,2,6*

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.

1 Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4 Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital Boston, Boston, MA 02115, USA.
5 Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
6 Howard Hughes Medical Institute, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: stuart_orkin{at}dfci.harvard.edu

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