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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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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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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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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DOI: https://doi.org/10.1038/ncb1914
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