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Read the Mostoslavsky Lab 2017-2018 Annual Report
Raul Mostoslavsky, MD, PhD The Laurel Schwartz Associate Professor of Oncology; Kristine and Bob Higgins MGH Research Scholar; Mass General Cancer Center Harvard Medical School Associate Member, The Broad Institute
Research in the Mostoslavsky laboratory focuses on a family of proteins ﬁrst discovered in yeast that plays a critical role in many human diseases, including cancer. The yeast protein Sir2 enables yeast cells to survive under conditions of nutrient stress and functions as a modulator of lifespan. While recent studies indicate that some of the mammalian sirtuin (SIRT) homologues also play a role in stress resistance and metabolic homeostasis, their precise molecular functions remain unclear. Most of our work involves the Sir2 mammalian homolog known as SIRT6. Our research indicates that SIRT6 modulates glucose metabolism and DNA repair and functions as a strong tumor suppressor gene. Using transgenic mouse models and other experimental systems, we are exploring the role of SIRT6 and metabolism in tumorigenesis and other disease processes, as well as trying to understand the crosstalk between metabolism and epigenetics.
Raul Mostoslavsky, MD, PhDPrincipal Investigator
*Graduate student**Undergraduate student
Cells need to maintain their nuclear DNA accurately in order to function properly. Indeed, defects in DNA integrity are associated with cancer, aging and immunodeﬁciency. Therefore, numerous DNA repair systems in mammalian cells function to endow us with long and relatively tumor-free lives. The DNA and the histones are arranged in the nucleus in a highly condensed structure known as chromatin. Cellular processes that unwind the double helix— such as transcription, replication and DNA repair—have to overcome this natural barrier to DNA accessibility.
Multicellular organisms also need to control their use of cellular energy stores. Glucose metabolism plays a crucial role in organismal homeostasis, inﬂuencing energy consumption, cell proliferation, stress resistance and lifespan. Defective glucose utilization causes numerous diseases ranging from diabetes to an increased tendency to develop tumors. For cells to respond appropriately to changes in energy status or to DNA damage, a close coupling of DNA repair, chromatin remodeling and metabolic pathways is likely to be involved.
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. In the past few years, we have been exploring the crosstalk between epigenetics and metabolism. In particular, our work has focused on mammalian Sir2 homologue, SIRT6. In recent years, we have identified SIRT6 as a key modulator of metabolism. Mice lacking SIRT6 exhibit severe metabolic defects, including hypoglycemia and hypoinsulinemia. SIRT6 appears to modulate glucose ﬂux inside the cells, functioning as a histone H3K9 deacetylase to silence glycolytic genes acting as a coexpressor of Hif1alpha, in this way directing glucose away from to reduce intracellular ROS levels. This function appears critical for glucose homeostasis, as SIRT6 deﬁcient animals die early in life from hypoglycemia.
Remarkably, SIRT6 acts as a tumor suppressor in colon cancer, regulating cancer metabolism through mechanisms that by-pass known oncogenic pathways. Cancer cells prefer fermentation (i.e., lactate production) to respiration. Despite being described by biochemist and Nobel laureate Otto Warburg decades ago (i.e., the Warburg effect), the molecular mechanisms behind this metabolic switch remain a mystery. We believe SIRT6 may function as a critical modulator of the Warburg effect, providing a long-sought molecular explanation to this phenomenon. We have also uncovered key roles for SIRT6 in DNA repair (anchoring the chromatin remodeler SNF2H to DNA breaks) and early development (acting as a repressor of pluripotent genes), indicating broad biological functions for this chromatin deacetylase. More recently, we identified SIRT6 as a robust tumor suppressor in pancreatic cancer, where it silences the oncofetal protein Lin28b, protecting against aggressive tumor phenotypes. As such, SIRT6 represents an example of a chromatin factor modulated by cancer cells to acquire "epigenetic plasticity".
Our current studies are directed at determining how the DNA repair and metabolic functions of SIRT6 may be related to each other. We are as well exploring novel metabolic liabilities in cancer, as well as broader chromatin roles in DNA repair. We use a number of experimental systems, including biochemical and biological approaches, as well as genetically engineered mouse models.
1. Deciphering how SIRT6 regulates chromatin structure2. Determining the role of SIRT6 in DNA repair and tumorigenesis using mouse models3. Elucidating the role of histone modiﬁcations and chromatin dynamics in DNA repair4. Determining molecular crosstalks between epigenetics and metabolism.5. Assessing metabolic liabilities in cancer and metastases
A Postdoctoral Research Fellow position is available to study the molecular function of the mammalian Sirtuin proteins, focusing on the role of SIRT6 in the metabolic response against genotoxic stress. The candidate is expected to have a PhD in the biological sciences, and be highly motivated and tenacious as a scientist, with experience in molecular biology, cell biology and biochemical techniques. The Fellow will have simultaneous academic appointment at the Massachusetts General Hospital and Harvard Medical School. The Fellow will develop innovative mouse gene-targeting technology to study SIRT6 function in vivo as a regulator of lifespan, tumorigenesis and homeostasis, as well as biochemical approaches aimed to understand the influence of SIRT6 in chromatin structure and DNA repair. The laboratory is located within an active intellectual environment in the Cancer Center and Harvard Stem Cell Institute, with strong ties throughout the institution, Harvard, and the MIT communities.
Please e-mail a brief cover letter and CV to:
Raul Mostoslavsky, MD, PhDAssociate Professor of MedicineMassachusetts General HospitalHarvard Medical SchoolSimches Research Building, CPZN 4200, 4th floorBoston, MA 02114Email: firstname.lastname@example.org
View a list of publications by researchers at the Mostoslavsky Laboratory
Kugel, S., Sebastian, C., Fitamant, J., Ross, K.N., Saha, S.K., Jain, E., Gladden, A., Arora, K.S., Kato, Y., Rivera, M.N., Ramaswamy, S., Sadreyev, R.I., Goren, A., Deshpande, V., Bardeesy, N., and Mostoslavsky, R. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell, 2016 Jun 2;165(6):1401-15.
Etchegaray JP, Chavez L, Huang Y, Ross KN, Choi J, Martinez-Pastor B, Walsh RM, Sommer CA, Lienhard M, Gladden A, Kugel S, Silberman DM, Ramaswamy S, Mostoslavsky G, Hochedlinger K, Goren A, Rao A, Mostoslavsky R. The histone deacety-lase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat Cell Biol. 2015 May;17(5):545-57.
Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L., Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, D’Urso A, Naar AM, Kingston R, Rippe K, and Mostoslavsky R. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Molecular Cell. 2013 Aug 22;51(4):454-68.
Sebastian C, Zwaans BM, Silberman DM, Gymrek MA, Goren A, Zhong L, Ran O, Truelove J, Guimaraes AR, Toiber D, Cosentino C, Greenson JK, MacDonald AI, McGlynn L, Maxwell F, Edwards J, Giacosa S, Guccione E, Weisledder R, Bernstein BE, Regev A, Shiels PG, Lombard DB and Mostoslavsky R. The Histone Deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012 Dec 7;151(6):1185-99.
Zhong L, D’Urso A, Toiber D, Sebas-tian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen L, Espinosa JM, Mostoslavsky R. The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1. Cell. 2010 Jan 22;140(2):280-93.
Mostoslavsky R, Chua KF, Lombard DL, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu J, Hong AL, Ford E, Cheng H-L, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopolous GD, and Alt FW. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006 Jan 27;124(2):315-29.
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