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Molecular and Cellular Biology, April 2001, p. 2413-2422, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2413-2422.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Site-Specific Acetylation by p300 or CREB Binding Protein Regulates Erythroid Krüppel-Like Factor Transcriptional Activity via Its Interaction with the SWI-SNF Complex

Wenjun Zhang,1 Shilpa Kadam,2 Beverly M. Emerson,2 and James J. Bieker1,*

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029,1 and Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 920372

Received 24 October 2000/Returned for modification 28 November 2000/Accepted 3 January 2001

Recruitment of modifiers and remodelers to specific DNA sites within chromatin plays a critical role in controlling gene expression. The study of globin gene regulation provides a convergence point within which to address these issues in the context of tissue-specific and developmentally regulated expression. In this regard, erythroid Krüppel-like factor (EKLF) is critical. EKLF is a red cell-specific activator whose presence is crucial for establishment of the correct chromatin structure and high-level transcriptional induction of adult beta -globin. We now find, by metabolic labeling-immunoprecipitation experiments, that EKLF is acetylated in the erythroid cell. EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain. Although site-specific DNA binding by EKLF is unaffected by the acetylation status of either of these lysines, directed mutagenesis of Lys-288 (but not Lys-302) decreases the ability of EKLF to transactivate the beta -globin promoter in vivo and renders it unable to be superactivated by coexpressed p300 or CBP. In addition, the acetyltransferase function of CBP or p300 is required for superactivation of wild-type EKLF. Finally, acetylated EKLF has a higher affinity for the SWI-SNF chromatin remodeling complex and is a more potent transcriptional activator of chromatin-assembled templates in vitro. These results demonstrate that the acetylation status of EKLF is critical for its optimal activity and suggest a mechanism by which EKLF acts as an integrator of remodeling and transcriptional components to alter chromatin structure and induce adult beta -globin expression within the beta -like globin cluster.

* Corresponding author. Mailing address: Mount Sinai School of Medicine, Department of Biochemistry and Molecular Biology, Box 1020, One Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 241-4143. Fax: (212) 860-9279. E-mail: james.bieker{at}mssm.edu.

Molecular and Cellular Biology, April 2001, p. 2413-2422, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2413-2422.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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