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Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing

Nature Cell Biology volume 11, pages 1010–1016 (2009)Cite this article

Abstract

The SNF2h (sucrose non-fermenting protein 2 homologue)-containing chromatin-remodelling complex NoRC silences a fraction of ribosomal RNA genes (rDNA) by establishing a heterochromatic structure at the rDNA promoter1,2,3. Here we show that the acetyltransferase MOF (males absent on the first) acetylates TIP5, the largest subunit of NoRC, at a single lysine residue, K633, adjacent to the TIP5 RNA-binding domain, and that the NAD+-dependent deacetylase SIRT1 (sirtuin-1) removes the acetyl group from K633. Acetylation regulates the interaction of NoRC with promoter-associated RNA (pRNA), which in turn affects heterochromatin formation, nucleosome positioning and rDNA silencing. Significantly, NoRC acetylation is responsive to the intracellular energy status and fluctuates during S phase. Activation of SIRT1 on glucose deprivation leads to deacetylation of K633, enhanced pRNA binding and an increase in heterochromatic histone marks. These results suggest a mechanism that links the epigenetic state of rDNA to cell metabolism and reveal another layer of epigenetic control that involves post-translational modification of a chromatin remodelling complex.

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Figure 1: MOF acetylates TIP5 in vitro and in vivo.
Figure 2: TIP5 acetylation is required for NoRC-mediated rDNA silencing.
Figure 3: Acetylation decreases pRNA binding to TIP5.
Figure 4: Deacetylation by SIRT1 is required for NoRC function.
Figure 5: Acetylation of TIP5 precedes replication of silent rRNA genes.

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Acknowledgements

We thank S. Smale for providing the vector pQXCIP, L. Guarente for expression vectors encoding SIRT1H355Y, G. Xouri and M. Gentzel for their contribution at the early stages of this work and M. Wilm for his support in the mass spectroscopic analysis. This study was funded by the Deutsche Forschungsgemeinschaft (SFB/Transregio 5, SP 'Epigenetics'), the EU-Network 'Epigenome' and the Fonds der Chemischen Industrie.

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  1. Yonggang Zhou and Kerstin-Maike Schmitz: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, Heidelberg, D-69120, Germany

    Yonggang Zhou, Kerstin-Maike Schmitz, Christine Mayer, Xuejun Yuan & Ingrid Grummt

  2. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    Asifa Akhtar

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  1. Yonggang Zhou
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Contributions

Y.G., K.S., C.M. and I.G. conceived the experiments and wrote the manuscript. Y.G., K.S., C.M. and X.Y. performed and analysed the experiments and generated the figures. A.A. contributed the reagents and materials.

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Correspondence to Ingrid Grummt.

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The authors declare no competing financial interests.

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Zhou, Y., Schmitz, KM., Mayer, C. et al. Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing. Nat Cell Biol 11, 1010–1016 (2009). https://doi.org/10.1038/ncb1914

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