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Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases

Nature Cell Biology volume 3, pages 114–120 (2001)Cite this article

Abstract

Histone modifications might act to mark and maintain functional chromatin domains during both interphase and mitosis. Here we show that pericentric heterochromatin in mammalian cells is specifically responsive to prolonged treatment with deacetylase inhibitors. These defined regions relocate at the nuclear periphery and lose their properties of retaining HP1 (heterochromatin protein 1) proteins. Subsequent defects in chromosome segregation arise in mitosis. All these changes can reverse rapidly after drug removal. Our data point to a crucial role of histone underacetylation within pericentric heterochromatin regions for their association with HP1 proteins, their nuclear compartmentalization and their contribution to centromere function.

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Figure 1: Treatment with a histone deacetylase inhibitor (TSA) reversibly induces the relocation of methylated pericentric heterochromatin towards the nuclear periphery.
Figure 2: Treatment with TSA reversibly induces the relocation of centromeric proteins at the nuclear periphery.
Figure 3: Perinuclear localization of centromeric regions is not observed at any phase of the cell cycle.
Figure 4: TSA treatment reversibly disrupts HP1α domains of concentration at pericentromeric regions.
Figure 5: Treatment with TSA induces a decrease in the Triton-resistant nuclear pool of HP1α, HP1β or HP1γ associated with pericentric heterochromatin.
Figure 6: Exogenous HP1α can be retained at pericentric heterochromatin in permeabilized control cells but not in TSA-treated cells.
Figure 7: TSA induces defective mitosis.

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Acknowledgements

We thank P. Chambon, B. Turner, C. Marheineke and A. Niveleau for providing antibodies, W. Earnshaw for the HP1–GST clone, ACA and anti-CENP-C antibodies, and J. Mello for critical reading. A.T. was supported by fellowships from the Ministère de l'Éducation Nationale et de l'Enseignement Supérieur de la Recherche et de la Technologie, l'Association de la Recherche sur le Cancer and the Human Frontier Science Foundation. This work was supported by EU TMR and by Ligue National contre le Cancer.

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  1. Institut Curie/Research section, UMR 218 du CNRS, 26 rue d'Ulm, Paris, cedex 05, 75248, France

    Angela Taddei, Christèle Maison, Danièle Roche & Geneviève Almouzni

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  1. Angela Taddei
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  2. Christèle Maison
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Correspondence to Geneviève Almouzni.

Supplementary information

Figure S1 DNA-synthesis inhibitors do not affect the localization of centromeres.

Figure S2  Three different inhibitors of histone deacetylases affect pericentric regions similarly to TSA. (PDF 197 kb)

Figure S3 Inhibition of DNA methylation with 5-azacytidine does not affect the association of HP1 with pericentric regions.

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Taddei, A., Maison, C., Roche, D. et al. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases. Nat Cell Biol 3, 114–120 (2001). https://doi.org/10.1038/35055010

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