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Control of Pancreas and Liver Gene Expression by HNF Transcription Factors
Duncan T. Odom,1Nora Zizlsperger,1,2D. Benjamin Gordon,1George W. Bell,1Nicola J. Rinaldi,1,2Heather L. Murray,1Tom L. Volkert,1Jörg Schreiber,1P. Alexander Rolfe,3David K. Gifford,3Ernest Fraenkel,1Graeme I. Bell,4Richard A. Young1,2*
The transcriptional regulatory networks that specify and maintainhuman tissue diversity are largely uncharted. To gain insightinto this circuitry, we used chromatin immunoprecipitation combinedwith promoter microarrays to identify systematically the genesoccupied by the transcriptional regulators HNF1, HNF4, and HNF6,together with RNA polymerase II, in human liver and pancreaticislets. We identified tissue-specific regulatory circuits formedby HNF1, HNF4, and HNF6 with other transcription factors, revealinghow these factors function as master regulators of hepatocyteand islet transcription. Our results suggest how misregulationof HNF4 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}wi.mit.edu
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