This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hatzis, P. Articles by Talianidis, I. Search for Related Content PubMed PubMed Citation Articles by Hatzis, P. Articles by Talianidis, I.

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.

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.

This article has been cited by other articles:

• Hatzis, P., van der Flier, L. G., van Driel, M. A., Guryev, V., Nielsen, F., Denissov, S., Nijman, I. J., Koster, J., Santo, E. E., Welboren, W., Versteeg, R., Cuppen, E., van de Wetering, M., Clevers, H., Stunnenberg, H. G. (2008). Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells. Mol. Cell. Biol. 28: 2732-2744 [Abstract] [Full Text]