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Molecular and Cellular Biology, October 2006, p. 7017-7029, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00297-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinase-Mediated Disruption of Enhancer-Promoter Communication Inhibits Hepatocyte Nuclear Factor 4 Expression

Pantelis Hatzis ,^, Irene Kyrmizi, and Iannis Talianidis^*

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Herakleion, Crete, Greece

Received 17 February 2006/ Returned for modification 3 April 2006/ Accepted 17 July 2006

Hepatocyte nuclear factor 4 (HNF-4) is a key member of the transcription factor network regulating hepatocyte differentiation and function. Activation of the HNF-4 gene involves physical interaction between a distant enhancer and the proximal promoter region, bound by distinct sets of transcription factors. Here we report that, upon mitogen-activated protein (MAP) kinase activation, HNF-4 expression is downregulated in human hepatoma cells. This effect is mediated by the loss of CEBP expression. During MAP kinase signaling, the recruitment of HNF-3ß and HNF-1 to the HNF-4 enhancer and RNA polymerase II to the proximal HNF-4 promoter was compromised. CBP, Brg1, and TFIIB were also dissociated from the HNF-4 regulatory regions, and the enhancer-promoter complex was disrupted. Interestingly, the extent of nucleosome acetylation did not decrease at either regulatory region, and HNF-6 and HNF-1, as well as components of the TFIID, remained associated with the proximal promoter during the repressed state. The results point to an absolute requirement of enhancer-promoter communication for maintaining the active state of the HNF-4 gene and provide evidence for a molecular bookmarking mechanism, which may contribute to the prevention of permanent silencing of the locus during the repressed state.

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* Corresponding author. Mailing address: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, P.O. Box 1385, Vassilika Vouton, 711 10 Herakleion, Crete, Greece. Phone: 30 2810 391163. Fax: 30 2810 391101. E-mail: talianid{at}imbb.forth.gr.

P.H. and I.K. contributed equally to this study.

Present address: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

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Molecular and Cellular Biology, October 2006, p. 7017-7029, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00297-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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