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J. Biol. Chem., Vol. 280, Issue 47, 39016-39023, November 25, 2005

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GATA-1 and Oct-1 Are Required for Expression of the Human -Hemoglobin-stabilizing Protein Gene^*

Patrick G. Gallagher1, Robert I. Liem, Ellice Wong, Mitchell J. Weiss¶, and David M. Bodine

From the Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8021, the ^¶Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the Hematopoiesis Section, NHGRI, National Institutes of Health, Bethesda, Maryland 20892-4442

-Hemoglobin-stabilizing protein (AHSP) is an erythroid protein that binds and stabilizes -hemoglobin during normal erythropoiesis and in pathological states of -hemoglobin excess. AHSP has been proposed as a candidate gene in some Heinz body hemolytic anemias and as a modifier gene in the -thalassemia syndromes. To gain additional insight into the molecular mechanisms controlling the erythroid-specific expression of the AHSP gene and provide the necessary tools for further genetic studies of these disorders, we have initiated identification and characterization of the regulatory elements controlling the human AHSP gene. We mapped the 5'-end of the AHSP erythroid cDNA and cloned the 5'-flanking genomic DNA containing the putative AHSP gene promoter. In vitro studies using transfection of promoter/reporter plasmids in human tissue culture cell lines, DNase I footprinting analyses and gel mobility shift assays, identified an AHSP gene erythroid promoter with functionally important binding sites for GATA-1- and Oct-1-related proteins. In transgenic mice, a reporter gene directed by a minimal human AHSP promoter was expressed in bone marrow, spleen, and reticulocytes, but not in nonerythroid tissues. In vivo studies using chromatin immunoprecipitation assays demonstrated hyperacetylation of the promoter region and occupancy by GATA-1. The AHSP promoter is an excellent candidate region for mutations associated with decreased AHSP gene expression.

Received for publication, June 3, 2005 , and in revised form, September 22, 2005.

^* This work was supported in part by Grants DK/HL62039 (to P. G. G.), HL65448 (to P. G. G.), and DK061692 (to M. J. W.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pediatrics, Yale University School of Medicine, 333 Cedar St., PO Box 208064, New Haven, CT 06520-8064. Tel.: 203-688-2896; Fax: 203-785-6974; E-mail: patrick.gallagher{at}yale.edu.

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