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Molecular and Cellular Biology, April 2002, p. 2505-2514, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2505-2514.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

BP1, a Homeodomain-Containing Isoform of DLX4, Represses the ß-Globin Gene

Michael B. Chase,1,{dagger} Sidong Fu,2 Susanne B. Haga,1,{ddagger} Gregory Davenport,2 Holly Stevenson,2 Khanh Do,2 Doris Morgan,3 Alex L. Mah,4 and Patricia E. Berg2*

Division of Human Genetics, University of Maryland School of Medicine,1 Department of Molecular and Cell Biology, University of Maryland, Baltimore, Maryland 21201;,4 Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C. 20037,2 Department of Medicine, MCP-Hahnemann University, Philadelphia, Pennsylvania 191023

Received 21 September 2001/ Returned for modification 14 November 2001/ Accepted 8 January 2002

In earlier studies we identified a putative repressor of the human ß-globin gene, termed beta protein 1 (BP1), which binds to two silencer DNA sequences upstream of the adult human ß-globin gene and to a negative control region upstream of the adult {delta}-globin gene. Further studies demonstrated an inverse correlation between the binding affinity of the BP1 protein for the distal ß-globin silencer sequence and the severity of sickle cell anemia, suggesting a possible role for BP1 in determining the production of hemoglobin S. We have now cloned a cDNA expressing the BP1 protein. Sequencing revealed that BP1 is a member of the homeobox gene family and belongs to the subfamily called Distal-less (DLX), genes important in early development. Further analysis showed that BP1 is an isoform of DLX4. BP1 protein has repressor function towards the ß-globin promoter, acting through the two ß-globin DNA silencers, demonstrated in transient transfection assays. Strong BP1 expression is restricted to placenta and kidney tissue, with no expression in 48 other human tissues. BP1 exhibits regulated expression in the human erythroid cell line MB-02, where its expression decreases upon induction of the ß-globin gene. BP1 is thus the first member of the DLX family with known DNA binding sites and a function in globin gene regulation.

* Corresponding author. Mailing address: The George Washington University Medical Center, Dept. of Biochemistry and Molecular Biology, Ross Building, Room 533, 2300 Eye St., N.W., Washington, DC 20037. Phone: (202) 994-2810. Fax: (202) 994-8974. E-mail: bcmpeb{at}gwumc.edu.

{dagger} Present address: American Red Cross, Holland Laboratory, Derwood, MD 20855.

{ddagger} Present address: National Institutes of Health, Office of Biotechnology Activities, Bethesda, MD 20892.

Molecular and Cellular Biology, April 2002, p. 2505-2514, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2505-2514.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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