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Molecular and Cellular Biology, October 2007, p. 7302-7314, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00758-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin Structure

Isabel Cuesta,^1,2, Kenneth S. Zaret,² and Pilar Santisteban^1*

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid 28029, Spain,¹ Cell and Developmental Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111²

Received 30 April 2007/ Returned for modification 29 May 2007/ Accepted 9 August 2007

The Forkhead box (Fox) transcription factors play diverse roles in differentiation, development, hormone responsiveness, and aging. A pioneer activity of the Forkhead factors in developmental processes has been reported, but how this may apply to other contexts of Forkhead factor regulation remains unexplored. In this study, we address the pioneer activity of the thyroid-specific factor FoxE1 during thyroid differentiation. In response to hormone induction, FoxE1 binds to the compacted chromatin of the inactive thyroperoxidase (TPO) promoter, which coincides with the appearance of strong DNase I hypersensitivity at the FoxE1 binding site. In vitro, FoxE1 can bind to its site even when this is protected by a nucleosome, and it creates a local exposed domain specifically on H1-compacted TPO promoter-containing nucleosome arrays. Furthermore, nuclear factor 1 binds to the TPO promoter simultaneously with FoxE1, and this binding has an additive effect on FoxE1-mediated chromatin structure alteration. On the basis of our findings, we propose that FoxE1 is a pioneer factor whose primary mechanistic role in mediating the hormonal regulation of the TPO gene is to enable other regulatory factors to access the chromatin. The presented model extends the reported pioneer activity of the Forkhead factors to processes involved in hormone-induced differentiation.

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* Corresponding author. Mailing address: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid 28029, Spain. Phone: 34-915854455. Fax: 34-915854401. E-mail: psantisteban{at}iib.uam.es

Published ahead of print on 20 August 2007.

Present address: Centro Nacional de Biotecnologia, CSIC, Madrid, Spain.

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Molecular and Cellular Biology, October 2007, p. 7302-7314, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00758-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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