SIRT6 links histone H3 lysine 9 deacetylation to control of NF-κB dependent gene expression and organismal lifespan

By Tiara L. A. Kawahara, E. Michishita, A. Adler, M. Damian, Elisabeth Berber, Meihong Lin, R. McCord, Kristine C. L. Ongaigui, Lisa D. Boxer, Howard Y. Chang and 1 more. Cell, 2009

1,097 citations recorded by the source corpus.

SUMMARY Members of the Sirtuin (SIRT) family of NAD+-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened lifespan 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.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/8379820b3ce465bd1c18b0548b5a84184ffc50c5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. Craig B. Thompson
2. Chao Lu
3. R. Mostoslavsky

In Molecular Biology

1. Aviv Regev
2. R. Medzhitov
3. T. Horng
4. Chao Lu
5. Amir Goren
6. Craig B. Thompson
7. Ralph Weissleder
8. Bradley E. Bernstein

In Physiology

1. R. Medzhitov
2. Aviv Regev
3. Craig B. Thompson
4. R. Mostoslavsky
5. T. Horng

Citations in the corpus

• THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM (2012, positive): “MYC has been described as a transcriptional activator of genes involved in ribosome biogenesis (van Riggelen et al., 2010), whereas we and others have described a role for SIRT6 as a transcriptional repressor (Kawahara et al., 2009; Zhong et al., 2010).”
• Transcriptional control of the inflammatory response (2009, background): “SIRT6 also inhibits NF-κB activity, but in this context NF-κB itself is not the target; instead, SIRT6 deacetylates H3K9 at the promoters of some NF-κB-regulated gene”
• Metabolic regulation of epigenetics (2012, background): “The substrates of sirtuins are diverse and among seven members of the mammalian sirtuin family, SIRT1 and SIRT6 have been shown to localize to the nucleus and exhibit HDAC activities (Imai et al., 2000; Kawahara et al., 2009).”
• The hallmarks of aging. (2013, neutral): “SIRT2 and SIRT6 may also downregulate the inflammatory response through deacetylation of NF-kB subunits and transcriptional repression of their target genes (Kawahara et al., 2009; Rothgiesser et al., 2010).”