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Science 303 (5662): 1378-1381

Copyright © 2004 by the American Association for the Advancement of Science

Control of Pancreas and Liver Gene Expression by HNF Transcription Factors

Duncan T. Odom,1 Nora Zizlsperger,1,2 D. Benjamin Gordon,1 George W. Bell,1 Nicola J. Rinaldi,1,2 Heather L. Murray,1 Tom L. Volkert,1 Jörg Schreiber,1 P. Alexander Rolfe,3 David K. Gifford,3 Ernest Fraenkel,1 Graeme I. Bell,4 Richard A. Young1,2*

Abstract: The transcriptional regulatory networks that specify and maintain human tissue diversity are largely uncharted. To gain insight into this circuitry, we used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1{alpha}, HNF4{alpha}, and HNF6, together with RNA polymerase II, in human liver and pancreatic islets. We identified tissue-specific regulatory circuits formed by HNF1{alpha}, HNF4{alpha}, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyte and islet transcription. Our results suggest how misregulation of HNF4{alpha} can contribute to type 2 diabetes.

1 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
2 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
3 MIT Laboratory of Computer Science, 200 Technology Square, Cambridge, MA 02139, USA.
4 Departments of Biochemistry and Molecular Biology, Medicine, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.

* To whom correspondence should be addressed. E-mail: young{at}

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N. Anderson and J. Borlak (2008)
Pharmacol. Rev. 60, 311-357
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Hepatocyte nuclear factor-1{alpha} regulates glucocorticoid receptor expression to control postnatal body growth.
W.-Y. Lin, Y.-J. Hu, and Y.-H. Lee (2008)
Am J Physiol Gastrointest Liver Physiol 295, G542-G551
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Global analysis of in vivo Foxa2-binding sites in mouse adult liver using massively parallel sequencing.
E. D. Wederell, M. Bilenky, R. Cullum, N. Thiessen, M. Dagpinar, A. Delaney, R. Varhol, Y. Zhao, T. Zeng, B. Bernier, et al. (2008)
Nucleic Acids Res. 36, 4549-4564
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On the origin of the {beta} cell.
J. M. Oliver-Krasinski and D. A. Stoffers (2008)
Genes & Dev. 22, 1998-2021
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Hepatocyte nuclear factor-4{alpha} is a central transactivator of the mouse Ntcp gene.
A. Geier, I. V. Martin, C. G. Dietrich, N. Balasubramaniyan, S. Strauch, F. J. Suchy, C. Gartung, C. Trautwein, and M. Ananthanarayanan (2008)
Am J Physiol Gastrointest Liver Physiol 295, G226-G233
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