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Retinoblastoma protein recruits histone deacetylase to repress transcription

Nature volume 391, pages 597–601 (1998)Cite this article

Abstract

The retinoblastoma protein (Rb) silences specific genes that are active in the S phase of the cell cycle and which are regulated by E2F transcription factors1. Rb binds to the activation domain of E2F and then actively represses the promoter by a mechanism that is poorly understood2,3. Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb ‘pocket’ domain. Association with the deacetylase is reduced by naturally occurring mutations in the pocket and by binding of the human papilloma virus oncoprotein E7. We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cycle protein cyclin E. Inhibition of histone deacetylase activity by trichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter. Our results indicate that histone deacetylases are important for regulating the cell cycle and that active transcriptional repression by Rb may involve the modification of chromatin structure.

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Figure 1: Rb associates with histone deacetylase activity in vitro and in vivo.
Figure 2: Rb interacts with histone deacetylases in vitro and in vivo.
Figure 3: Rb recruits HDAC1 to E2F.
Figure 4: Histone deacetylase is required for full Rb-mediated transcriptional repression in vivo.

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Acknowledgements

This work is dedicated to the memory of Danny Spiegelhalter who died of retinoblastoma. We thank C. Hassig and S. L. Schreiber for the 1121 and 1123 HCAC1 antibodies and for technical advice on peptide acetylation and histone deacetylase assay; S. Critchlow for the gift of XRCC4 protein; W. Zwerschke and P. Janssen-Duerr for the CycE reporter construct; N. Mermod for the 3T3/208 cell line and M. O'Connor for technical advice on GST microcolumns. This work was funded by a Cancer Research Campaign programme grant, by an MRC grant and by an EC Biomed2 grant. A.B. was supported by a grant from the Association for International Cancer Research; D.J.McC. was funded by an American Cancer Society International Cancer research fellowship. E.A.M. was supported by a CRC studentship; J.L.R. was funded by an MRC studentship.

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  1. Wellcome/CRC Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK

    Alexander Brehm, Eric A. Miska, Dennis J. McCance, Juliet L. Reid, Andrew J. Bannister & Tony Kouzarides

  2. Department of Microbiology and Immunology, University of Rochester, Rochester, 14642, New York, USA

    Dennis J. McCance

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  1. Alexander Brehm
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Correspondence to Tony Kouzarides.

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Brehm, A., Miska, E., McCance, D. et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597–601 (1998). https://doi.org/10.1038/35404

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