View article

In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1–Sirt7) have been implicated as NAD⁺-dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in …