SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1α activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.
Bibliographical noteFunding Information:
This work was supported by the V Foundation (R.M.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from AFAR (R.M.), A New Investigator Award from The Massachusetts Life Sciences Center (R.M.), a P&F Award from the Joslin Diabetes Center (R.M.), and Grant P30 DK57521 from the Metabolic Physiology Core (BADERC). D.T. is supported by a fellowship from the Brain Power for Israel Fund. Y.D. is supported by JDRF. J.M.E. is supported by NIH-RO1 CA117907 and the Howard Hughes Medical Institute. We thank Magali Silberman, Daniel Holoch, Pere Puigserver, John Dominy, Matthew Vander Heiden, Mike Zimmer, David Lombard, Bjoern Schwer, Fred Alt, Katrin Chua, and members of the Bardeesy, Hochedlinger, Hock, and Ramaswamy labs for reagents and helpful discussions. We thank Kelly Shay, Laura Prickett-Rice, and Kate Folz-Donahue for technical assistance. We are also thankful to Nabeel Bardeesy and Hanno Hock for critically reading the manuscript and Jose Polo for assistance with the ChIP assays.