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| Subject Categories: Chromatin & Transcription | Differentiation & Death |
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| The EMBO Journal
(2005) 24, 3313–3324, doi:10.1038/sj.emboj.7600802 Published online 1 September 2005 |
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| The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation |
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| Lionel Gresh1, Brigitte Bourachot1, Andreas Reimann1, Bruno Guigas2, Laurence Fiette3, Serge Garbay1, Christian Muchardt1, Louis Hue2, Marco Pontoglio1, Moshe Yaniv1 and Agnès Klochendler-Yeivin4 |
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1 Unité Expression Génétique et Maladies—CNRS FRE 2850, Département de Biologie du Développement, Institut Pasteur, Paris, France 2 Hormone and Metabolic Research Unit, Christian de Duve Institute of Cellular Pathology, UCL, Brussels, Belgium 3 Unité de Recherche et d'Expertise en Histotechnologie et Pathologie, Institut Pasteur, Paris, France 4 Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem, Israel To whom correspondence should be addressed Moshe Yaniv, Unité Expression Génétique et Maladies—CNRS FRE 2850, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: +33 1 4568 8512; Fax: +33 1 4061 3033; E-mail: yaniv@pasteur.fr Received 8 December 2004; Accepted 5 August 2005; Published online 1 September 2005. |
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| Abstract |
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| Regulation of gene expression underlies cell differentiation and organogenesis. Both transcription factors and chromatin modifiers are crucial for this process. To study the role of the ATP-dependent SWI/SNF chromatin-remodeling complex in cell differentiation, we inactivated the gene encoding the core complex subunit SNF5/INI1 in the developing liver. Hepatic SNF5 deletion caused neonatal death due to severe hypoglycemia; mutant animals fail to store glycogen and have impaired energetic metabolism. The formation of a hepatic epithelium is also affected in SNF5-deficient livers. Transcriptome analyses showed that SNF5 inactivation is accompanied by defective transcriptional activation of 70% of the genes that are normally upregulated during liver development. These include genes involved in glycogen synthesis, gluconeogenesis and cell–cell adhesion. A fraction of hepatic developmentally activated genes were normally expressed, suggesting that cell differentiation was not completely blocked. Moreover, SNF5-deleted cells showed increased proliferation and we identified several misexpressed genes that may contribute to cell cycle deregulation in these cells. Our results emphasize the role of chromatin remodeling in the activation of cell-type-specific genetic programs and driving cell differentiation. |
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| Keywords: cell differentiation, Cre-loxP, INI1, proliferation, transcriptome |
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