Abstract
The sirtuin Sirt6 is a NAD-dependent histone deacetylase that is implicated in gene regulation and lifespan control. Sirt6 can interact with the stress-responsive transcription factor NF-κB and regulate some NF-κB target genes, but the full scope of Sirt6 target genes as well as dynamics of Sirt6 occupancy on chromatin are not known. Here we map Sirt6 occupancy on mouse promoters genome-wide and show that Sirt6 occupancy is highly dynamic in response to TNF-α. More than half of Sirt6 target genes are only revealed upon stress-signaling. The majority of genes bound by NF-κB subunit RelA recruit Sirt6, and dynamic Sirt6 relocalization is largely driven in a RelA-dependent manner. Integrative analysis with global gene expression patterns in wild-type, Sirt6−/−, and double Sirt6−/− RelA−/− cells reveals the epistatic relationships between Sirt6 and RelA in shaping diverse temporal patterns of gene expression. Genes under the direct joint control of Sirt6 and RelA include several with prominent roles in cell senescence and organismal aging. These data suggest dynamic chromatin relocalization of Sirt6 as a key output of NF-κB signaling in stress response and aging.
Highlights
Silent Information Regulator-2 (Sir2) encodes an NAD-dependent histone deacetylase that links chromatin regulation to genomic stability, gene silencing and lifespan in yeast
Both the departure and arrival of Sirt6 alter gene expression, shaping the temporal dynamics of NF-kB transcriptional response and directly controlling the expression of other key regulators of aging. These findings provide the first view of how an oscillatory transcription factor can drive a progression of chromatin changes over time
Genes jointly controlled by Sirt6 and NF-kB should include important contributors to aging, but to date, the identity of relevant target genes are not known
Summary
Silent Information Regulator-2 (Sir2) encodes an NAD-dependent histone deacetylase that links chromatin regulation to genomic stability, gene silencing and lifespan in yeast. The chromatin-associated sirtuin, SIRT6, is an important regulator of gene expression and genome integrity [8,9,10,11,12,13]. SIRT6 deacetylates lysine 9 and 56 of histone H3 (H3K9Ac and H3K56Ac), and its deacetylase activity is involved in inhibition of gene expression [9,10], [12]. SIRT6 deacetylates H3K9Ac and destabilizes RELA occupancy, leading to termination of NF-kB-dependent gene expression [10]. It is unclear whether this model applies generally to most or to only select NF-kB target genes. The full set of genes targeted by SIRT6 remains to be determined
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