SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation

Abstract

In contrast to stably repressive, constitutive heterochromatin and stably active, euchromatin, facultative heterochromatin has the capacity to alternate between repressive and activated states of transcription1. As such, it is an instructive source to understand the molecular basis for changes in chromatin structure that correlate with transcriptional status. Sirtuin 1 (SIRT1) and suppressor of variegation 3–9 homologue 1 (SUV39H1) are amongst the enzymes responsible for chromatin modulations associated with facultative heterochromatin formation. SUV39H1 is the principal enzyme responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in regions of heterochromatin2. SIRT1 is an NAD+-dependent deacetylase that targets histone H4 at lysine 16 (refs 3 and 4), and through an unknown mechanism facilitates increased levels of H3K9me3 (ref. 3). Here we show that the mammalian histone methyltransferase SUV39H1 is itself targeted by the histone deacetylase SIRT1 and that SUV39H1 activity is regulated by acetylation at lysine residue 266 in its catalytic SET domain. SIRT1 interacts directly with, recruits and deacetylates SUV39H1, and these activities independently contribute to elevated levels of SUV39H1 activity resulting in increased levels of the H3K9me3 modification. Loss of SIRT1 greatly affects SUV39H1-dependent H3K9me3 and impairs localization of heterochromatin protein 1. These findings demonstrate a functional link between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1.

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Figure 1: The histone lysine methyltransferase SUV39H1 interacts with catalytically active SIRT1 in vitro and in vivo.
Figure 2: SIRT1 upregulates SUV39H1 activity in vitro and in vivo through the SIRT1 N terminus.
Figure 3: Acetylation of SUV39H1 negatively regulates its activity and is elevated in nicotinamide-treated cells.
Figure 4: SIRT1 and SUV39H1 activities are linked in vivo.

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Acknowledgements

We thank T. Jenuwein for sharing expression plasmids for wild-type and mutant versions of SUV39H1 and SUV39H1 MEF cells (wild type and -/-); F. W. Alt for SIRT1 MEF cells (wild type and -/-); P. Trojer and other members of the Reinberg laboratory for discussions; L. Vales for comments on the manuscript; K. Cabane for technical assistance; and L. Lacomis for help with mass spectrometric analysis. This work was supported by the NIH and HHMI (D.R.) and the NCI Cancer Center (P.T.).

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Correspondence to Danny Reinberg.

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The file contains Supplementary Figures S1-S6 with legends and additional references. (PDF 1647 kb)

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Vaquero, A., Scher, M., Erdjument-Bromage, H. et al. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440–444 (2007). https://doi.org/10.1038/nature06268

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