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SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-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-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-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-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.

Pubmed ID: 19135889


  • Kawahara TL
  • Michishita E
  • Adler AS
  • Damian M
  • Berber E
  • Lin M
  • McCord RA
  • Ongaigui KC
  • Boxer LD
  • Chang HY
  • Chua KF



Publication Data

January 9, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: K08 AG028961
  • Agency: NIA NIH HHS, Id: K08 AG028961-03
  • Agency: NIA NIH HHS, Id: R01 AG028867
  • Agency: NIA NIH HHS, Id: R01 AG028867-04
  • Agency: NCI NIH HHS, Id: R01 CA118750
  • Agency: NCI NIH HHS, Id: R01 CA118750-02
  • Agency: NCI NIH HHS, Id: R01 CA118750-03

Mesh Terms

  • Acetylation
  • Animals
  • Cell Line
  • Chromatin
  • Crosses, Genetic
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental
  • Humans
  • Longevity
  • Mice
  • NF-kappa B
  • Promoter Regions, Genetic
  • Sirtuins
  • Transcription Factor RelA