Expression of rRNA genes is coupled to the overall metabolism of the cell by the NAD-dependent histone deacetylase SIRT1, a component of the Energy-dependent Nucleolar Silencing Complex (eNoSC) (Murayama et al. 2008, reviewed in Salminen and Kaarniranta 2009, Grummt and Voit 2010). eNoSC comprises Nucleomethylin (NML), SIRT1, and the histone methylase SUV39H1 (Murayama et al. 2008). Deacetylation and methylation of histone H3 in the chromatin of a rRNA gene by eNoSC causes reduced expression of the gene. When glucose is low, NAD is high (NADH is low), activity of SIRT1 is high, and activity of rRNA genes is reduced. It is hypothesized that eNoSC forms on a nucleosome containing dimethylated lysine-9 on histone H3 (H3K9me2) and then eNoSC deacetylates and dimethylates the adjacent nucleosome, thus catalyzing spreading of H3K9me2 throughout the gene.
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The Sirtuin-1 (SIRT1) component of eNoSC deacetylates histone H3 at lysine-9 (Vaquero et al. 2004, Murayama et al. 2008). The reaction uses nicotinamide adenine dinucleotide (NAD) as the acceptor of the acetyl group and generates nicotinamide and 1-O-acetyl-ADP-ribose as products (Vaquero et al. 2004). The use of NAD links the reaction to the overall energy balance of the cell. Cells exposed to high glucose have a greater NADH:NAD ratio and therefore lower activity of eNoSC (Murayama et al. 2008). Low glucose produces higher NAD and higher activity of eNoSC.
The SUV39H1 component of eNoSC dimethylates histone H3 at lysine-9 (Murayama et al. 2008). The reaction depends on the prior deacetylation reaction catalyzed by the SIRT1 component of eNoSC. Histone H3 dimethylated at lysine-9 inhibits expression of rRNA genes.
RRP8 (Nucleomethylin, NML), SIRT1, and SUV39H1 form the energy-dependent Nucleolar Silencing Complex (eNoSC) at inactive rRNA genes (Murayama et al. 2008). RRP8 is constitutively located in the nucleolus (Yang et al. 2013), binds histone H3 dimethylated at lysine-9 (Murayama et al. 2008) and appears to recruit SIRT1 from the nucleoplasm to the nucleolus (Yang et al. 2013). The eNoSC binds chromatin throughout the rRNA transcription unit. SIRT1 may deacetylate and, hence, activate SUV39H1 but this has not yet been shown at rDNA. Abrogation of any member of eNoSC interferes with binding of the other members of the complex. The eNoSC complex appears to cause spreading of heterochromatin at rDNA.
RRP8 (Nucleomethylin, NML) recruits SIRT1 to the nucleolus to form the energy-dependent Nucleolar Silencing Complex (eNoSC), which induces chromatin changes that inhibit rRNA transcription. RRP8 can bind 5S RNA (transcribed by RNA ploymerase III), 5.8S rRNA, and 28S rRNA and the bound RNA prevents RRP8 from binding SIRT1 (Yang et al. 2013). Thus the level of 5S RNA, 5.8S rRNA, and 28S rRNA in the nucleus negatively regulates the assembly of eNoSC, coupling transcriptional regulation of rRNA to epigenetic silencing of rRNA genes.
As inferred from mouse, SIRT1, an NAD+ dependent deacetylase, deacetylates the TAF1B (TAF(1)68) subunit of the SL1 complex. Deacetylation of TAF1B inhibits transcription of rRNA genes.
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