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J. Biol. Chem., Vol. 282, Issue 2, 853-862, January 12, 2007

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Purification and Identification of Proteins That Bind to the Hereditary Persistence of Fetal Hemoglobin –198 Mutation in the -Globin Gene Promoter^*

Ivan A. Olave¹, Catalin Doneanu, Xiangdong Fang, George Stamatoyannopoulos, and Qiliang Li²

From the Department of Medicine, Division of Medical Genetics, and the Mass Spectrometry Center, Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195

Expression of the -globin gene is silenced in adult humans. However, certain point mutations in the -globin gene promoter are capable of maintaining expression of this gene during adult erythropoiesis, a condition called non-deletion hereditary persistence of fetal hemoglobin (HPFH). Among these, the British form of HPFH carrying a T C point mutation at position –198 of the ^A-globin gene promoter results in 4–10% fetal hemoglobin in heterozygotes. In this study, we used nuclear extracts from murine erythroleukemia cells to purify a protein complex that binds the HPFH –198 -globin gene promoter. Members of this protein complex were identified by mass spectrometry and include DNMT1, the transcriptional coactivator p52, the protein SNEV, and RAP74 (the largest subunit of the general transcription factor IIF). Sp1, which was previously considered responsible for HPFH –198 -globin gene activation, was not identified. The potential role of these proteins in the reactivation and/or maintenance of -globin gene expression in the adult transcriptional environment is discussed.

Received for publication, November 8, 2006

^* This work was supported by National Institutes of Health Grants DK61805 and HL73439 (to Q. L.) and Grant DK45365 (to G. S.). 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 Present address: Blue Heron Biotechnology, Inc., Bothell, WA 98021.

² To whom correspondence should be addressed: Div. of Medical Genetics, University of Washington, P. O. Box 357720, Seattle, WA 98195. Tel.: 206-616-4526; Fax: 206-616-4527; E-mail: li111640{at}u.washington.edu.

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