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Dr. Mostoslavsky studied Medicine in Argentina, where hereceived his MD Degree in 1993. After finishing medical school, he realized hewanted to pursue a career in research, so he moved to Israel for PhD studies inmolecular biology. He studied the molecular mechanisms that underlie allelicexclusion, a phenomenon by which each lymphocyte expresses only one of the twoimmunoglobulin gene copies. He discovered that such a process involves achromatin change that differentiates one allele from the other, namely DNAdemethylation and asynchronous replication. This work was published in Genes& Development, Nature Genetics, and Nature.

He then moved to Boston to pursue post-doctoral trainingunder the supervision of Prof. Frederick W. Alt. His interest in recombinationand chromatin got him interested in studying the role of proteins called SIRTs,which are homologs of the yeast NAD deacetylase Sir2, involved in regulatingDNA recombination, transcription, and lifespan. There are seven homologs inmammals, called SIRT1-7. He has generated mice deficient for each one of them.He has focused on characterizing the function of the SIRT6 protein as a modelchromatin modulator of metabolism. He has found that SIRT6 is achromatin-associated protein, and SIRT6 deficiency leads to genomic instabilityand defects in DNA repair in cells. Mice lacking SIRT6 show signs of aging-likephenotypes, suggesting that SIRT6 might be the real ortholog for the yeastprotein. Those studies have been published in Cell.

Since he started his independent laboratory, he and hiscolleagues have been focusing on understanding the precise role for SIRT6 inmodulating glucose homeostasis and cancer metabolism. They have found thatSIRT6 functions as a histone deacetylase to modulate expression of multipleglycolytic genes. In this context, SIRT6 deacetylates H3K9 at the promoters ofmultiple glycolytic genes, inhibiting their expression working as aco-repressor of Hif1alpha. In the absence of SIRT6, glycolysis is activated andmitochondrial respiration inhibited (Zhong et al., Cell 2010). This is acritical switch to allow survival under nutrient stress, and a hallmark switchin cancer metabolism (Warburg Effect). Indeed, they have followed up hisoriginal observations and demonstrated that SIRT6 functions as a tumorsuppressor by inhibiting the Warburg effect (Sebastian et al., Cell 2012).

In addition, they have known for years that SIRT6deficient cells accumulate genomic instability (Mostoslavsky et al., Cell2006), yet the reason behind this phenotype was unknown. They have found thatSIRT6 interacts with the chromatin remodeler SNF2h, recruiting SNF2H to sitesof DNA breaks, in this way increasing chromatin accessibility to DNA repairfactors for efficient DNA repair (Toiber et al., Mol. Cell 2013). Morerecently, they found that SIRT6 also plays a key role in early embryonicdevelopment, repressing expression of pluripotent genes to allow properdifferentiation into the three germ layers (Etchegaray et al., Nat. Cell Biol.2015).