Vaquero, A. et al. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440-444

Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Jersey 08854, USA.
Nature (Impact Factor: 41.46). 12/2007; 450(7168):440-4. DOI: 10.1038/nature06268
Source: PubMed


In contrast to stably repressive, constitutive heterochromatin and stably active, euchromatin, facultative heterochromatin has the capacity to alternate between repressive and activated states of transcription. 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 heterochromatin. 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.

Download full-text


Available from: Hediye Erdjument-Bromage, Apr 29, 2015
  • Source
    • "Because of this, SIRT1 acts as a fuel-sensing molecule that allows the cell to respond to both reduction and increases in nutrient availability (Vaquero and Reinberg, 2009; Shoba et al., 2009; Ruderman et al., 2010). At the chromatin level, SIRT1 promotes the formation of facultative heterochromatin (Vaquero et al., 2007) (a tightly packed chromatin region that can be dynamically and reversibly restored to the more open conformation of euchromatin). SIRT1 changes chromatin structure by deacetylating histone 4 at lysine 16 (H4K16) and histone 3 at lysine 9 (H3K9ac) Vaquero and Reinberg, 2009, two histone marks associated with gene activation (Wang et al., 2008; Ruthenburg et al., 2007; Guttman et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Substantial progress has been made in recent years towards deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty.
    Frontiers in Neuroendocrinology 08/2014; 36. DOI:10.1016/j.yfrne.2014.08.003 · 7.04 Impact Factor
  • Source
    • "This link between heterochromatin and sumoylation was further supported by elegant studies in a mammalian model system (19,22). Sirtuin 1 (SIRT1) mediated deacetylation of Suv39H1 plays a positive role in its enzymatic activity and protein level (23). This modulation may prevent Mouse Double Minute 2 (MDM2)-mediated polyubiquitination and degradation, thereby contributing to genome protection in response to stress signals (24). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although several studies have suggested that the functions of heterochromatin regulators may be regulated by post-translational modifications during cell cycle progression, regulation of the histone methyltransferase Suv39H1 is not fully understood. Here, we demonstrate a direct link between Suv39H1 phosphorylation and cell cycle progression. We show that CDK2 phosphorylates Suv39H1 at Ser391 and these phosphorylation levels oscillate during the cell cycle, peaking at S phase and maintained during S-G2-M phase. The CDK2-mediated phosphorylation of Suv39H1 at Ser391 results in preferential dissociation from chromatin. Furthermore, phosphorylation-mediated dissociation of Suv39H1 from chromatin causes an enhanced occupancy of JMJD2A histone demethylase on heterochromatin and alterations in inactive histone marks. Overexpression of phospho-mimic Suv39H1 induces early replication of heterochromatin, suggesting the importance of Suv39H1 phosphorylation in the replication of heterochromatin. Moreover, overexpression of phospho-defective Suv39H1 caused altered replication timing of heterochromatin and increases sensitivity to replication stress. Collectively, our data suggest that phosphorylation-mediated modulation of Suv39H1-chromatin association may be an initial step in heterochromatin replication.
    Nucleic Acids Research 04/2014; 42(10). DOI:10.1093/nar/gku263 · 9.11 Impact Factor
  • Source
    • "SIRT1 has also been shown to regulate gene expression via CpG methylation [29], [31], [32] and histone modifications [33], [34]. We therefore determined if SIRT1 regulates TERT expression via these epigenetic mechanisms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.
    PLoS ONE 01/2014; 9(1):e84931. DOI:10.1371/journal.pone.0084931 · 3.23 Impact Factor
Show more