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Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer

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Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications in the Biological Sciences Papers in the Biological Sciences 2014 Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer Giuseppe Lo Sasso Ecole Polytechnique Fédérale de Lausanne Dongryeol Ryu Ecole Polytechnique Fédérale de Lausanne Laurent Mouchiroud Ecole Polytechnique Fédérale de Lausanne Samodha C. Fernando University of Nebraska-Lincoln, [email protected] Christopher L. Anderson University of Nebraska-Lincoln See next page for additional authors Follow this and additional works at: https://digitalcommons.unl.edu/bioscifacpub Part of the Biology Commons Sasso, Giuseppe Lo; Ryu, Dongryeol; Mouchiroud, Laurent; Fernando, Samodha C.; Anderson, Christopher L.; Katsyuba, Elena; Piersigilli, Alessandra; Hottiger, Michael O.; Schoonjans, Kristina; and Auwerx, Johan, "Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer" (2014). Faculty Publications in the Biological Sciences. 366. https://digitalcommons.unl.edu/bioscifacpub/366 This Article is brought to you for free and open access by the Papers in the Biological Sciences at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications in the Biological Sciences by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Giuseppe Lo Sasso, Dongryeol Ryu, Laurent Mouchiroud, Samodha C. Fernando, Christopher L. Anderson, Elena Katsyuba, Alessandra Piersigilli, Michael O. Hottiger, Kristina Schoonjans, and Johan Auwerx This article is available at DigitalCommons@University of Nebraska - Lincoln: https://digitalcommons.unl.edu/ bioscifacpub/366 Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer Giuseppe Lo Sasso1, Dongryeol Ryu1, Laurent Mouchiroud1, Samodha C. Fernando2, Christopher L. Anderson2,3, Elena Katsyuba1, Alessandra Piersigilli1,4, Michael O. Hottiger5, Kristina Schoonjans6, Johan Auwerx1* 1 Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland, 2 Department of Animal Science, University of Nebraska, Lincoln, Nebraska, United States of America, 3 School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, United States of America, 4 Institute of Animal Pathology, University of Bern, Bern, Switzerland, 5 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland, 6 Institute of Bioengineering, School of Life Science, Ecole Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland Abstract Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis- associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int2/2) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC. Citation: Lo Sasso G, Ryu D, Mouchiroud L, Fernando SC, Anderson CL, et al. (2014) Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer. PLoS ONE 9(7): e102495. doi:10.1371/journal.pone.0102495 Editor: Salvatore Papa, Institute of Hepatology - Birkbeck, University of London, United Kingdom Received May 20, 2014; Accepted June 19, 2014; Published July 11, 2014 Copyright: ß 2014 Lo Sasso et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: GLS is supported by an Outgoing Italian Association for Cancer Research (AIRC)/Marie Curie Fellowship. JA KS laboratory is supported by grants from the E´cole Polytechnique Fe´de´rale de Lausanne, the EU Ideas program (AdG-231138), the Swiss National Science Foundation (31003A-140780 and 310030-143748), the Krebsforschung Schweiz (KFS-3082-02-2013 and KFS-2809-08-2011), and NIH (R01AG043930). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] Introduction Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase [8], is involved in a wide range of cellular processes including metabo- Paneth and goblet cells are highly specialized small intestinal lism, cell proliferation and apoptosis, and immune response [9]. epithelial cells that synthesize and secrete anti-microbial peptides The role of SIRT1 in the regulation of intestinal homeostasis is and mucus. These factors represent the first line of defense against only beginning to be elucidated. Recently an involvement of pathogens and are essential to maintain the subtle balance among intestinal SIRT1 in systemic bile acid and cholesterol metabolism different bacterial species that colonize the mammalian gut [1]. has been proposed [10]. Furthermore, studies focusing on the role Dysbiotic microbiota impact on the health of the host and of SIRT1 in colorectal cancer development using Apcmin/+ mice as contribute to the pathogenesis of several intestinal diseases, such as a model, showed conflicting results supporting both tumor inflammatory bowel disease (IBD) and colitis-associated colorectal promoting [11] and tumor suppressing [12,13] functions. cancer (CAC) [2]. Using mice with an intestinal-specific Sirt1 deletion (Sirt1int2/2), The differentiation and maturation of Paneth and goblet cells we show here that SIRT1 regulates Paneth and goblet cell is controlled by the Wnt and Notch signaling cascades that maturation and production of anti-bacterial proteins. These effects cooperate to promote the specification of the different cell lineages depend on SIRT1-mediated changes in the acetylation status of [3]. Moreover, the SAM pointed domain containing ETS SPDEF. Moreover, intestinal Sirt1 deletion has a major impact on transcription factor (SPDEF), a downstream effector of both Wnt the gut microbiome and protects mice from IBD and CAC. and Notch pathways, is known to enhance the differentiation of Notably, the effects of Sirt1 deficiency on the production of anti- both Paneth and goblet cells from their common progenitor [4]. bacterial proteins are evolutionary conserved in C.elegans high- SPDEF was initially identified as a regulator of the prostate- lighting the ancient nature of this function of SIRT1. Taken specific antigen [5], but later also associated to breast, lung, and together our results suggest that targeting SIRT1 may be of intestine epithelium, with possible involvement in cancer progres- interest for the management of IBD and CAC. sion in those tissues [6,7]. PLOS ONE | www.plosone.org 1 July 2014 | Volume 9 | Issue 7 | e102495 Loss of Sirt1 Function Improves Intestinal Physiology Materials and Methods mRNA extraction and RT-qPCR analysis int2/2 int2/2 RNA was isolated from tissues using the TriPure reagent Generation of Sirt1 and Sirt1 (Roche) according with manufacturer’s instructions. cDNA was EGFP-ires-CRE-ert2 -LGR5 mice generated from 1 mg of total RNA using QuantiTect Reverse L2/L2 For the generation of Sirt1 floxed (Sirt1 ) mice, genomic Transcription Kit (Qiagen). qRT-PCR was carried out using DNA covering the Sirt1 locus was amplified from the 129Sv strain LightCycler 480 SYBR Green I Master Mix (Roche) and analyzed by high-fidelity PCR. The resulting DNA fragments were through DDCT calculation. Values were normalized to Cyclophi- assembled into the targeting vector of the Institut Clinique de la lin expression. Primers are listed in Table S1 in File S1. Souris (Strasbourg, France). The construct in which exons 5, 6 and 7 were flanked by LoxP sites was then electroporated into 129Sv Luciferase assay embryonic stem (ES) cells (Figure S1B). G418-resistant colonies PC3 cells (ATCC) in 96/wells plates were co-transfected with a were selected and analyzed for homologous recombination by reporter containing the SPDEF response element of the human E- PCR and positive clones were verified by Southern blot cadherin promoter, pGL2Basic-EcadK1 and pcDNA3, pCDA3- hybridization. Correctly targeted ES cell clones were injected into FLAG-SPDEF or pCDA3-FLAG-SPDEFK294Q with or without blastocysts and transferred into pseudopregnant females, resulting pUSE-SIRT1 expression vectors (jetPEI transfection; Polyplus). in chimeric offspring that were mated to female C57BL/6J mice Media was removed after 24 hr, cells washed with cold PBS, and that express the Flp recombinase under the control of the Luciferase Substrate (Bright-Glo Luciferase Assay System, Pro- ubiquitous cytomegalovirus promoter [14]. Offspring that trans- mega) was added before Luciferase measurement by the Victor mitted
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