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Science 25 October 2002:
Vol. 298. no. 5594, pp. 799 - 804
DOI: 10.1126/science.1075090
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Research Articles

Transcriptional Regulatory Networks in Saccharomyces cerevisiae

Tong Ihn Lee,1* Nicola J. Rinaldi,12* François Robert,1* Duncan T. Odom,1 Ziv Bar-Joseph,3 Georg K. Gerber,3 Nancy M. Hannett,1 Christopher T. Harbison,12 Craig M. Thompson,1dagger Itamar Simon,1 Julia Zeitlinger,1 Ezra G. Jennings,12 Heather L. Murray,1 D. Benjamin Gordon,1 Bing Ren,1ddagger John J. Wyrick,1§ Jean-Bosco Tagne,1 Thomas L. Volkert,1 Ernest Fraenkel,1 David K. Gifford,3 Richard A. Young12parallel

We have determined how most of the transcriptional regulators encoded in the eukaryote Saccharomyces cerevisiae associate with genes across the genome in living cells. Just as maps of metabolic networks describe the potential pathways that may be used by a cell to accomplish metabolic processes, this network of regulator-gene interactions describes potential pathways yeast cells can use to regulate global gene expression programs. We use this information to identify network motifs, the simplest units of network architecture, and demonstrate that an automated process can use motifs to assemble a transcriptional regulatory network structure. Our results reveal that eukaryotic cellular functions are highly connected through networks of transcriptional regulators that regulate other transcriptional regulators.

1 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 MIT Laboratory of Computer Science, 200 Technology Square, Cambridge, MA 02139, USA.
*   These authors contributed equally to this work.

dagger    Present address: Akceli Inc., 1 Hampshire Street, Cambridge, MA 02139, USA.

ddagger    Present address: Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA 92093, USA.

§   Present address: California Institute of Technology, Pasadena, CA 91125, USA.

parallel    To whom correspondence should be addressed. E-mail: young{at}wi.mit.edu

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   Abstract »    Full Text »    PDF »
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