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 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.

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

“…Besides the histone substrates and many other nuclear factors, SIRT1 also deacetylates chromatin-modifying enzymes, including PCAF, p300, TIP60 and SUV39H1 [10,[30][31][32]. In this study, we identified hMOF as another substrate of SIRT1.…”

Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis

“…Sirt1 belongs to the family of the mammalian homologues of the Sir2 (silent information regulator-2) of the yeast Saccharomyces cerevisiae. This is a NAD + -dependent protein deacetylase, present in cell cytoplasm and nucleus, that modulates the cell cycle, senescence, apoptosis, and metabolism by distinct mechanisms that include regulation of expression of individual genes (Picard et al 2004), condensation of chromatin (Vaquero et al 2007), or deacetylation of specific transcription factors (Brunet et al 2004). Milne and Denu (2008) described protective action of Sirt1 in aged endothelium, heart, liver, and adipose tissue, while others reported pro-aging roles of sirtuins (Longo 2009), which may be due to specific time and tissue properties of Sirt1 activity.…”

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…To further elucidate the role of Sirt7 on Sirt1, we wanted to explore whether Sirt7 also controls other Sirt1 effects on heterochromatin. Interestingly, in an overexpression system, we observed that Sirt7 co-immunoprecipitates with the histone methyltransferase Suv39h1 (Figure 1(A)), which is bound and activated by Sirt1 [20,22] suggesting formation of a tripartite Sirt7/Sirt1/Suv39h1 complex. Co-immunoprecipitation experiments in primary mouse embryonic fibroblasts (MEFs) confirmed that endogenous Sirt7 and Suv39h1 form a molecular complex (Figure 1(B)).…”

“…Since Sirt1 positively regulates Suv39h1 activity [20] and Sirt1 becomes autodeacetylated at K230 and hyperactive in Sirt7 deficient cells [19], we speculated that hyperactivation of Sirt1 plays the decisive role for increased Suv39h1 activity in Sirt7 depleted cells. To corroborate this assumption, we expressed different combination of Sirt1, Sirt7 and Suv39h1 in HEK293T cells and monitored H3K9me3 levels.…”

“…We demonstrate that the presence of hyperactive Sirt1 in Sirt7 deficient cells leads to permanent activation of the histone methyltransferase Suv39h1, a known target of Sirt1 [20], which subsequently results in higher histone 3 lysine 9 trimethylation (H3K9me3) levels within the repetitive pericentromeric heterochromatin.…”