Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.


  1. Craig, J. M. Heterochromatin—many flavours, common themes. Bioessays 27, 17–28 (2005)

    Article  CAS  Google Scholar 

  2. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004)

    Article  CAS  Google Scholar 

  4. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    Article  ADS  CAS  Google Scholar 

  5. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002)

    Article  CAS  Google Scholar 

  6. Shankaranarayana, G. D., Motamedi, M. R., Moazed, D. & Grewal, S. I. Sir2 regulates histone H3 lysine 9 methylation and heterochromatin assembly in fission yeast. Curr. Biol. 13, 1240–1246 (2003)

    Article  CAS  Google Scholar 

  7. Sewalt, R. G. et al. Selective interactions between vertebrate polycomb homologs and the SUV39H1 histone lysine methyltransferase suggest that histone H3–K9 methylation contributes to chromosomal targeting of Polycomb group proteins. Mol. Cell. Biol. 22, 5539–5553 (2002)

    Article  CAS  Google Scholar 

  8. Sauve, A. A., Wolberger, C., Schramm, V. L. & Boeke, J. D. The biochemistry of sirtuins. Annu. Rev. Biochem. 75, 435–465 (2006)

    Article  CAS  Google Scholar 

  9. Monneret, C. Histone deacetylase inhibitors. Eur. J. Med. Chem. 40, 1–13 (2005)

    Article  CAS  Google Scholar 

  10. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002)

    Article  CAS  Google Scholar 

  11. Min, J., Zhang, X., Cheng, X., Grewal S. I & Xu, R. M. Structure of the SET domain histone lysine methyltransferase Clr4. Nature Struct. Biol. 9, 828–832 (2002)

    CAS  PubMed  Google Scholar 

  12. Melcher, M. et al. Structure–function analysis of SUV39H1 reveals a dominant role in heterochromatin organization, chromosome segregation, and mitotic progression. Mol. Cell. Biol. 20, 3728–3741 (2000)

    Article  CAS  Google Scholar 

  13. Vaquero, A. et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20, 1256–1261 (2006)

    Article  CAS  Google Scholar 

  14. Winkler, G. S. et al. Isolation and mass spectrometry of transcription factor complexes. Methods 26, 260–269 (2002)

    Article  CAS  Google Scholar 

  15. Nishioka, K. et al. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell 9, 1201–1213 (2002)

    Article  CAS  Google Scholar 

  16. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001)

    Article  CAS  Google Scholar 

  17. Cheng, H. L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA. 100, 10794–10799 (2003)

    Article  ADS  CAS  Google Scholar 

Download references


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.).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Danny Reinberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing