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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
-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
-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
-globin expression
within the
-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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