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Published Online December 4, 2008
Science DOI: 10.1126/science.1165409

Reports

Submitted on September 3, 2008
Accepted on November 12, 2008

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

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

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

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

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.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)