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Molecular and Cellular Biology, August 2006, p. 5759-5770, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00271-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mechanism of Action of a Distal NF-{kappa}B-Dependent Enhancer

Belete Teferedegne,{dagger} Myesha R. Green, Zhu Guo,{ddagger} and Jeremy M. Boss*

Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322

Received 13 February 2006/ Returned for modification 20 March 2006/ Accepted 5 May 2006

The monocyte chemoattractant protein 1 gene (MCP-1) is regulated by TNF through an NF-{kappa}B-dependent distal enhancer and an Sp1-dependent promoter-proximal regulatory region. In the silent state, only the distal regulatory region is accessible to transcription factors. Upon activation by tumor necrosis factor, NF-{kappa}B binds to the distal regulatory region and recruits CBP and p300. CBP and p300 recruitment led to specific histone modifications that ultimately enabled the binding of Sp1 to the proximal regulatory region. During this process, a direct interaction between the distal and proximal regulatory regions occurred. Sp1, NF-{kappa}B, CBP, and p300 were required for this interaction. CBP/p300-mediated histone modifications enhanced the binding of the coactivator CARM1 to the distal regulatory region. CARM1, which is necessary for MCP-1 expression, was not required for distal-proximal region interactions, suggesting that it plays a later downstream activation event. The results describe a model in which the separation of the distal enhancer from the promoter-proximal region allows for two independent chromatin states to exist, preventing inappropriate gene activation at the promoter while at the same time allowing rapid induction through the distal regulatory region.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Phone: (404) 727-5973. Fax: (404) 727-1719. E-mail: boss{at}microbio.emory.edu.

{dagger} Present address: Rowett Research Institute, Greenburn, Bucksburn, AB21 9SB, Aberdeen, Scotland, United Kingdom.

{ddagger} Present address: Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333.

Molecular and Cellular Biology, August 2006, p. 5759-5770, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00271-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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