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The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing

Oncogene volume 27, pages 1449–1460 (2008)Cite this article

Abstract

EZH2 is a Polycomb group (PcG) protein that promotes the late-stage development of cancer by silencing a specific set of genes, at least in part through trimethylation of associated histone H3 on Lys 27 (H3K27). Nuclear inhibitor of protein phosphatase-1 (NIPP1) is a ubiquitously expressed transcriptional repressor that has binding sites for the EZH2 interactor EED. Here, we examine the contribution of NIPP1 to EZH2-mediated gene silencing. Studies on NIPP1-deficient cells disclose a widespread and essential role of NIPP1 in the trimethylation of H3K27 by EZH2, not only in the onset of this trimethylation during embryonic development, but also in the maintenance of this repressive mark in proliferating cells. Consistent with this notion, EZH2 and NIPP1 silence a common set of genes, as revealed by gene-expression profiling, and NIPP1 is associated with established Polycomb target genes and with genomic regions that are enriched in Polycomb targets. Furthermore, most NIPP1 target genes are trimethylated on H3K27 and the knockdown of either NIPP1 or EZH2 is often associated with a loss of this modification. Our data reveal that NIPP1 is required for the global trimethylation of H3K27 and is implicated in gene silencing by EZH2.

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Acknowledgements

Fabienne Withof provided expert technical assistance. This work was financially supported by the Fund for Scientific Research-Flanders (Grant G.0290.05 and ZKB6003-01-W01), a Flemish Concerted Research Action and the Prime Minister's office (IAP/V-05). The microscopy was performed in the Cell Imaging Core Facility of KULeuven.

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Author notes

  1. M Nuytten, L Beke and A Van Eynde: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Cell Biology, Laboratory of Biosignaling & Therapeutics, Faculty of Medicine, KULeuven, Leuven, Belgium

    M Nuytten, L Beke, A Van Eynde, H Ceulemans, M Beullens & M Bollen

  2. MicroArray Facility—VIB, Leuven, Belgium

    P Van Hummelen

  3. Laboratory of Cancer Epigenetics, Faculty of Medicine, Free University of Brussels, Leuven, Belgium

    F Fuks

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  1. M Nuytten
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Correspondence to A Van Eynde.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Nuytten, M., Beke, L., Van Eynde, A. et al. The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing. Oncogene 27, 1449–1460 (2008). https://doi.org/10.1038/sj.onc.1210774

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