[HTML][HTML] SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span

TLA Kawahara, E Michishita, AS Adler, M Damian… - Cell, 2009 - cell.com
TLA Kawahara, E Michishita, AS Adler, M Damian, E Berber, M Lin, RA McCord…
Cell, 2009cell.com
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-κB signaling. SIRT6 interacts
with the NF-κB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target
gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters …
Summary
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-κB signaling. SIRT6 interacts with the NF-κB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-κB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-κB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-κB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-κB signaling may contribute to premature and normal aging.
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