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.
Kawahara
Tiara L A
TL
Program in Epithelial Biology, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.
Michishita
Eriko
E
Adler
Adam S
AS
Damian
Mara
M
Berber
Elisabeth
E
Lin
Meihong
M
McCord
Ron A
RA
Ongaigui
Kristine C L
KC
Boxer
Lisa D
LD
Chang
Howard Y
HY
Chua
Katrin F
KF
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008136:Longevity / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C501860:Sirt6 protein, mouse; D037761:Sirtuins