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J. Biol. Chem., Vol. 280, Issue 5, 3715-3722, February 4, 2005

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Identification of Transcriptional Networks during Liver Regeneration^*

Peter White, John E. Brestelli, Klaus H. Kaestner, and Linda E. Greenbaum¶

From the Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

The molecular analysis of mammalian cellular proliferation in vivo is limited in most organ systems by the low turnover and/or the asynchronous nature of cell cycle progression. A notable exception is the partial hepatectomy model, in which quiescent hepatocytes reenter the cell cycle and progress in a synchronous fashion. Here we have exploited this model to identify regulatory networks operative in the mammalian cell cycle. We performed microarray-based expression profiling on livers 0-40 h post-hepatectomy corresponding to G₀, G₁, and S phases. Differentially expressed genes were identified using the statistical analysis program PaGE (Patterns from Gene Expression), which was highly accurate as confirmed by quantitative reverse transcription-PCR of randomly selected targets. A shift in the transcriptional program from genes involved in lipid and hormone biosynthesis in the quiescent liver to those contributing to cytoskeleton assembly and DNA synthesis in the proliferating liver was demonstrated by biological theme analysis. In a novel approach, we employed computational pathway analysis tools to identify specific regulatory networks operative at various stages of the cell cycle. This allowed us to identify a large cluster of genes controlling mitotic spindle assembly and checkpoint control at the 40-h time point as regulated at the mRNA level in vivo.

Received for publication, September 21, 2004 , and in revised form, November 9, 2004.

^* This work was supported by NIDDK National Institutes of Health Grants R01-56669 (to L. E. G.) and U01-56947 (to K. H. K.), as well as the Functional Genomics Core of the Penn Diabetes Center and the Molecular Biology Core of the Penn Center for Molecular Studies in Liver and Digestive Diseases. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked `advertisement' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1S and 2S.

^¶ To whom correspondence should be addressed: Dept. of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., Clinical Research Bldg. 675A, Philadelphia, PA 19104. Tel.: 215-573-1868; Fax: -215-573-2024; E-mail: greenbal{at}mail.med.upenn.edu.

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