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J. Biol. Chem., Vol. 279, Issue 40, 41477-41486, October 1, 2004

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Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1^*

Quan Zhao, Helen Cumming, Loretta Cerruti, John M. Cunningham, and Stephen M. Jane¶

From the Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Victoria 3050 Australia and the Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Acetylation provides one mechanism by which the functional diversity of individual transcription factors can be expanded. This is valuable in the setting of complex multigene loci that are regulated by a limited number of proteins, such as the human -globin locus. We have studied the role of acetylation in the regulation of the transcription factor NF-E4, a component of a protein complex that facilitates the preferential expression of the human -globin genes in fetal erythroid cells. We have shown that NF-E4 interacts directly with, and serves as a substrate for, the acetyltransferase co-activator PCAF. Acetylation of NF-E4 is restricted to a single residue (Lys⁴³) in the amino-terminal domain of the protein and results in two important functional consequences. Acetylation of NF-E4 prolongs the protein half-life by preventing ubiquitin-mediated degradation. This stabilization is PCAF-dependent, since enforced expression in fetal/erythroid cells of a mutant form of PCAF lacking the histone acetyltransferase domain (PCAFHAT) decreases NF-E4 stability. Acetylation of Lys⁴³ also reduces the interaction between NF-E4 and HDAC1, potentially maximizing the activating ability of the factor at the -promoter. These results provide further demonstration that co-activators, such as PCAF, can influence individual transcription factor properties at multiple levels to alter their effects on gene expression.

Received for publication, May 10, 2004 , and in revised form, July 21, 2004.

^* This work was supported by National Health and Medical Research Council of Australia, NIH Grants PO1 HL53749-03 and RO1 HL69232-01 (to S. M. J.), the Wellcome Trust (to S. M. J.), Cancer Centre Support CORE Grant P30 CA 21765, the American Lebanese Syrian Associated Charities, and the Assisi Foundation of Memphis. 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.

^¶ To whom correspondence should be addressed: Rotary Bone Marrow Research Laboratory, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, Victoria 3050, Australia. Tel.: 61-3-93428641; Fax: 61-3-93428634; E-mail: jane{at}wehi.edu.au.

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