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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.10.045 Byline: Henrietta Szutorisz (1), Andrew Georgiou (1), Laszlo Tora (2), Niall Dillon (1) Abstract: The ability of stem cells to activate different gene expression programs requires the choreographed assembly of trans-acting factors at enhancers and promoters during cell differentiation. In this study, we show that the proteasome acts on specific regulatory regions in embryonic stem (ES) cells to prevent incorrect transcriptional initiation. Chemical or siRNA-mediated inhibition of proteasome activity results in increased transcription factor and RNA polymerase II binding and leads to activation of cryptic promoters. Analysis of the binding profiles of different proteasome subunits in normal ES cells and following RNAi knockdown of individual subunits provides evidence for a targeted assembly of the 26S proteasome at specific regulatory elements. Our results suggest that the proteasome promotes a dynamic turnover of transcription factor and Pol II binding at tissue-specific gene domains in ES cells, thereby restricting permissive transcriptional activity and keeping the genes in a potentiated state, ready for activation at later stages. Author Affiliation: (1) Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, UK (2) Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS UMR 7104, INSERM, ULP, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France Article History: Received 13 April 2006; Revised 28 August 2006; Accepted 13 October 2006 Article Note: (miscellaneous) Published: December 28, 2006

The different types of model that can explain pluripotency at the level of gene are examined. A novel epigenetic model is proposed to explain how genes are primed in embryonic stem cells to express at later stages of development.

Activation of eukaryotic genes requires a tight temporal control of trans-acting-factor binding to different types of sequence elements. General transcription factors (GTFs) have a central role in the regulation of RNA polymerase II (Pol II) function because they are involved in the initiation of transcription at all class II promoters. Recent studies have shown that GTFs and Pol II are recruited to enhancer elements and that this binding is an early event in gene activation. We propose that an important role of some enhancers is to function as nucleation centres for the assembly of the pre-initiation complex to regulate the timing of gene activation during development, differentiation and the cell cycle.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tibs.2005.08.006 Byline: Henrietta Szutorisz (a), Niall Dillon (a), Laszlo Tora (b) Abstract: Activation of eukaryotic genes requires a tight temporal control of trans-acting-factor binding to different types of sequence elements. General transcription factors (GTFs) have a central role in the regulation of RNA polymerase II (Pol II) function because they are involved in the initiation of transcription at all class II promoters. Recent studies have shown that GTFs and Pol II are recruited to enhancer elements and that this binding is an early event in gene activation. We propose that an important role of some enhancers is to function as nucleation centres for the assembly of the pre-initiation complex to regulate the timing of gene activation during development, differentiation and the cell cycle. Author Affiliation: (a) Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, UK (b) Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM, UMR 7104 CNRS, ULP, 1, rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France