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Molecular and Cellular Biology, August 2002, p. 5626-5637, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5626-5637.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4

Sohail Malik,* Annika E. Wallberg, Yun Kyoung Kang, and Robert G. Roeder

Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021

Received 26 December 2001/ Returned for modification 13 February 2002/ Accepted 2 May 2002

The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) regulates the expression of many liver-specific genes both during development and in the adult animal. Towards understanding the molecular mechanisms by which HNF-4 functions, we have established in vitro transcription systems that faithfully recapitulate HNF-4 activity. Here we have focused on the coactivator requirements for HNF-4, especially for the multicomponent TRAP/SMCC/Mediator complex that has emerged as the central regulatory module of the transcription apparatus. Using a system that has been reconstituted from purified transcription factors, as well as one consisting of unfractionated nuclear extract from which TRAP/SMCC/Mediator has been depleted by specific antibodies, we demonstrate a strong dependence of HNF-4 function on this coactivator. Importantly, we further show a TRAP/SMCC/Mediator-dependence for HNF-4 transcriptional activation from chromatin templates. The latter involves cooperation with the histone acetyltransferase-containing coactivator p300, in accord with a synergistic mode of action of the two divergent coactivators. We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically. This interaction likely involves primary HNF-4 activation function 2 (AF-2)-dependent interactions with the TRAP220 subunit of TRAP/SMCC/Mediator and secondary (AF-2-independent) interactions with TRAP170/RGR1. Finally, recruitment experiments using immobilized templates strongly suggest that the functional consequences of the physical interaction probably are manifested at a postrecruitment step in the activation pathway.

* Corresponding author. Mailing address: Laboratory of Biochemistry and Molecular Biology The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-7605. Fax: (212) 327-7949. E-mail: maliks{at}rockvax.rockefeller.edu.

Molecular and Cellular Biology, August 2002, p. 5626-5637, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5626-5637.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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