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Molecular and Cellular Biology, October 2009, p. 5413-5425, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00368-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter{triangledown}

Sergey Belikov, Carolina Åstrand,{dagger} and Örjan Wrange*

Department of Cell and Molecular Biology, Karolinska Institutet, P.O. Box 285, SE-17177 Stockholm, Sweden

Received 23 March 2009/ Returned for modification 22 April 2009/ Accepted 8 August 2009

Reconstitution of the glucocorticoid receptor (GR)-regulated mouse mammary tumor virus (MMTV) promoter in Xenopus oocytes was used to monitor the effects of different transcription factor contexts. Three constitutively binding factors, nuclear factor 1 (NF1), octamer transcription factor 1 (Oct1), and the Forkhead box A1 (FoxA1), were shown to act in concert, to direct the chromatin structure, and to enhance the GR response. FoxA1 has a dominant effect in the absence of hormone and induces a cluster of DNase I-hypersensitive sites in the segment comprising bp –400 to +25. This FoxA1-mediated chromatin remodeling does not induce MMTV transcription, as opposed to that of the GR. However, the robust FoxA1-dependent chromatin opening has the following drastic functional consequences on the hormone regulation: (i) GR-DNA binding is facilitated, as revealed by dimethyl sulfate in vivo footprinting, leading to increased hormone-induced transcription, and (ii) the GR antagonist RU486 is converted into a partial agonist in the presence of FoxA1 via ligand-independent GR activation. We conclude that FoxA1 mediates a preset chromatin structure and directs a context-specific response of a nuclear receptor. Furthermore, the alternative nucleosome arrangement induced by GR and FoxA1 implies this to be determined by constitutive binding of transcription factors rather than by the DNA sequence itself.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, The Medical Nobel Institute, Box 285, Karolinska Institutet, SE-17177 Stockholm, Sweden. Phone: 46 8 52487373. Fax: 46 8 323672. E-mail: orjan.wrange{at}ki.se

{triangledown} Published ahead of print on 17 August 2009.

{dagger} Present address: Wellcome Trust/CR UK Gurdon Institute, Tennis Court Road, University of Cambridge, CB2 1QN Cambridge, United Kingdom.

Molecular and Cellular Biology, October 2009, p. 5413-5425, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00368-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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