Raul Mostoslavsky, M.D., Ph.D.

The histone deacetylase SIRT6 mediates crosstalk between epigenetics and metabolism

Our lab is interested in understanding the influence of chromatin on DNA repair, and the relationship between the DNA damage response and the metabolic adaptation of cells. We focus on the study of a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. Sir2 is a chromatin silencer that functions as an NAD- dependent histone deacetylase to inhibit DNA transcription and recombination. We have found that one of the mammalian Sir2 homologues, SIRT6, binds to chromatin and regulates DNA repair as a modulator of chromatin accessibility. In addition, we have shown that SIRT6 regulates metabolic responses in cells, and that mice lacking SIRT6 exhibit severe metabolic defects, including a fatal hypoglycemia. SIRT6 modulates glucose flux inside the cells, directing glucose away of glycolysis and into the mitochondria. In this regard, SIRT6 functions as a critical modulator of cellular stress, regulating glucose metabolism as a co-repressor of Hif1a. In the presence of nutrients, SIRT6 binds Hif1a and deacetylates H3K9 at Hif1a target promoters, thereby suppressing Hif1a-dependent transcriptional activation of these genes. Under conditions of nutrient stress, SIRT6 is inactivated, enabling a Hif1a-dependent response with increased glucose uptake, enhanced glycolysis and inhibition of mitochondrial respiration. In recent studies, we have uncovered a role for SIRT6 as a tumor suppressor, preventing a shift toward glycolytic metabolism in cancer cells (Warburg Effect). We are currently investigating whether the roles for SIRT6 in metabolism and DNA repair are linked, namely whether SIRT6 coordinates metabolic adaptations in the context of DNA damage. As well, we are investigating in vivo, using SIRT6 conditional mice, the precise role for SIRT6 in controlling glucose and lipid metabolism in specific tissues (in particular skeletal muscle and adipose tissue). Finally, we are investigating the crosstalk between chromatin dynamics and mitochondrial metabolism, trying to dissect whether availability of metabolites, such as Acetyl-CoA and methionine, may influence histone and DNA modifications.

References.

1. Finkel, T., Deng, C-H., and Mostoslavsky, R. (2009). Recent Progress in the biology and physiology of sirtuins. Nature 460, 587-591. PMCID: PMC3727385

2. Zhong, L., D’Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A., Marinelli, B., Wikstrom, J.D., Nir, T., Clish, C.B., Vaitheesvaran, Iliopoulos, O., B., Kurland, I., Dor, Y., Weissleder, R., Shirihai, O.S., Ellisen, L., Espinosa, J.M., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293. PMCID: PMC2821045

3. Sebastian, C., Zwaans, B.M., Silberman, D.M., Gymrek, M.A., Goren, A., Zhong, L., Ran, O., Truelove, J., Guimaraes, A.R., Toiber, D., Cosentino, C., Greenson, J.K., MacDonald, A.I., McGlynn, L., Maxwell, F., Edwards, J., Giacosa, S., Guccione, E., Weisledder, R., Bernstein, B.E., Regev, A., Shiels, P.G., Lombard, D.B. and Mostoslavsky, R. (2012). The Histone Deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199. PMCID: PMC3526953

4. Jiang, H., Khan, S., Wang, Y., Charron, G., He, B., Sebastian, C., Du, J., Kim, R., Ge, E., Mostoslavsky, R., Hang, H.C., Hao, Q., and Lin, H. (2013). SIRT6 regulates TNF-a secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110-113. PMCID: PMC3635073

5. Martinez-Pastor B, Cosentino C, Mostoslavsky R. (2013). A tale of metabolites: the cross-talk between chromatin and energy metabolism. Cancer Discov. 3(5):497-501. PMCID: PMC3652636

6. Dominy JE Jr, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman J, Pierce K, Mostoslavsky R, Denu JM, Clish CB, Yang X, Shulman GI, Gygi SP, Puigserver P.The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis. Mol Cell. 2012;48:900-13.PMCID: PMC3534905

 

 

 

 

 

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