Figure 6. Model for Sirt6 regulation of targeting and gene expression.

Sirt6 occupies the promoters of a wide array of genes, likely in conjunction with other transcription factors. We propose that upon the addition of a stress such as TNF-α, Sirt6 redistributes to promoters via its interaction with RelA. This redistribution enables derepression of a subset of genes (e.g. Mapk2, Fbxo4) and induction of repression of genes involved in pathways such as aging (Cdkn2a, Lmna), DNA damage response (Gadd45b), and NF-κB feedback (Nfkbia, Nfkb2). The experience of NF-κB activation may influence subsequent rounds of stress response by creating a new basal state of Sirt6 occupancy.