SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-B-Dependent Gene Expression and Organismal Life Span
Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-B signaling. SIRT6 interacts with the NF-B RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-B target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-B-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-B-driven gene expression programs in multiple Sirt6-deficient tissues invivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-B signaling via H3K9 deacetylation at chromatin, and hyperactive NF-B signaling may contribute to premature and normal aging.
doi:10.1016/j.cell.2008.10.052
Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-B signaling. SIRT6 interacts with the NF-B RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-B target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-B-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-B-driven gene expression programs in multiple Sirt6-deficient tissues invivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-B signaling via H3K9 deacetylation at chromatin, and hyperactive NF-B signaling may contribute to premature and normal aging.
doi:10.1016/j.cell.2008.10.052