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1. Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors

Author

Morgane Bourmaud, Anda Huna, Ikrame Naciri, Marthe Laisné, Pierre-Antoine Defossez, Selene Di Carlo, Nikhil Gupta, David Bernard, Lucie Peduto, Laure Ferry, Olivier Kirsh, Nadine Martin, Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stroma, inflammation et réparation tissulaire - Stroma, Inflammation and Tissue Repair, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [EpiCALC 2013 to P.A.D. and D.B.], Institut National du Cancer [PLBio15–013 to P.A.D. and D.B.], Labex ‘Who am I?’ [ANR-11-LABX-0071 under ANR-11-IDEX-005–02, to P.A.D.], European Research Council [ERC648428-PERIF to L.P.], Fondation ARC [4th-year PhD scholarship to I.N., Programme Labellisé PGA1/RF20180206807 to P.A.D.], Fondation pour la Recherche Médicale [postdoctoral fellowship to A.H.]. The open access publication charge for this paper has been waived by Oxford University Press - NAR Editorial Board members are entitled to one free paper per year in recognition of their work on behalf of the journal., The authors thanks the Genomics Platform of Institut Curie for Nanostring analysis. The Nanostring platform of Institut Curie was initiated with the support of French grants (LabEx and EquipEx): ANR-10-IDEX-0001–02 PSL, ANR-11-LBX-0044 and « INCa-DGOS- 4654 » SIRIC11–002. We thank Valérie Doye, Stéphanie Bolhy, and Philippe Girard at Institut Jacques Monod for help with the Incucyte. Concerning the lentiviral vector production, we acknowledge Christophe Huret and the Paris Diderot Vectorology Platform of Paris Diderot University, Sorbonne Paris Cité, CNRS UMR 7216, Paris, France. We acknowledge the kind help of Elisabeth Brambilla with some experiments that do not appear in the submitted version of the manuscript. For the gift of reagents we acknowledge the kind contribution of Katrin Chua, Philippe Chavrier, Annabelle Decottignies, Sébastien Jauliac and Michael Kracht. Finally, we thank the following colleagues for useful discussions: Jean-Marc Vanacker, Robert Dante, Nathalie Théret, Saadi Khochbin, Céline Prunier, Céline Vallot, Claire Rougeulle, Isabelle Bernard-Pierrot, Slimane Ait-si-ali, Jonathan Weitzman, Valérie Lallemand-Mezger, ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 648428,H2020,ERC-2014-CoG,PERIF(2015), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM), Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), École pratique des hautes études (EPHE), Centre de Recherche en Cancérologie de Lyon (CRCL), Stroma, inflammation et réparation tissulaire, ATMEL [Rousset], Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), TOMASSO DEVERGE, Carina, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Perivascular cells at the crossroads of inflammation, regeneration and fibrosis - PERIF - - H20202015-11-01 - 2020-10-31 - 648428 - VALID

Subjects
Transcription, Genetic, [SDV]Life Sciences [q-bio], ADAM12 Protein, Triple Negative Breast Neoplasms, Biology, Protein Serine-Threonine Kinases, Cell Line, Transforming Growth Factor beta1, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Cell Line, Tumor, Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Genetics, Humans, Epigenetics, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Histone Acetyltransferases, Regulation of gene expression, 0303 health sciences, Gene regulation, Chromatin and Epigenetics, Chromatin, Cell biology, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Organ Specificity, Cancer cell, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Interference, 030217 neurology & neurosurgery, Genetic screen, Signal Transduction
Abstract

International audience; The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiased approach to test the ability of 350 distinct genetic or epigenetic perturbations to induce the illegitimate expression of over 40 tissue-restricted genes in primary human cells. We find that almost all of these genes are remarkably resistant to reactivation by a single alteration in signaling pathways or chromatin regulation. However, a few genes differ and are more readily activated; one is the placenta-expressed gene ADAM12, which promotes invasion. Using cellular systems, an animal model, and bioinformatics, we find that a non-canonical but druggable TGF-β/KAT2A/TAK1 axis controls ADAM12 induction in normal and cancer cells. More broadly, our data show that illegitimate gene expression in cancer is an heterogeneous phenomenon, with a few genes activatable by simple events, and most genes likely requiring a combination of events to become reactivated.

Published
2019

2. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

Author

Jelena Melesina, Wolfgang Sippl, Tino Heimburg, Christophe Romier, Martin Marek, Karin Schmidtkunz, E. Ramos-Morales, Julien Lancelot, C. Da Veiga, Manfred Jung, Takayoshi Suzuki, Dina Robaa, Eric Ennifar, Dmitrii V. Kalinin, T.B. Shaik, Raymond J. Pierce, Alokta Chakrabarti, Ralph Holl, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Martin-Luther-Universität Halle Wittenberg (MLU), Albert-Ludwigs-Universität Freiburg, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Münster, Kyoto Prefectural University of Medicine [Kyoto, Japon], Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Hamburg, This work and the authors of this paper have been supported by funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreements nos. 241865 (SEtTReND) and 602080 (A-ParaDDisE) as well as the German Research Foundation (DFG) to W.S. (Si868/13-1) and M.J. (Ju295/13-1). This study was supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. C.R., M.M., T.B.S., E.R.M., and R.J.P. are supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg, the Institut Pasteur de Lille and the Université de Lille. W.S. was supported by the European Regional Development Fund of the European Commission. We acknowledge the support and the use of resources of the French Infrastructure for Integrated Structural Biology FRISBI ANR-10-INBS-05 and of Instruct-ERIC, We thank members of the ESRF-EMBL joint structural biology groups, the SOLEIL, and the Swiss Light Source (SLS) synchrotrons for the use of their beamline facilities and for help during data collection. We are grateful to Alastair McEwen (IGBMC) for his kind assistance during X-ray data collections., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), European Project: 241865,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,SETTREND(2010), European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Westfälische Wilhelms-Universität Münster = University of Münster (WWU)

Subjects
0301 basic medicine, Indoles, [SDV]Life Sciences [q-bio], Molecular Dynamics Simulation, Hydroxamic Acids, Isozyme, Histone Deacetylases, Substrate Specificity, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Catalytic Domain, Drug Discovery, Hydrolase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Amino Acid Sequence, Tyrosine, biology, Chemistry, Active site, HDAC8, Protein engineering, Triazoles, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Repressor Proteins, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine
Abstract

International audience; Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1–L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

Published
2018

3. Tumour heterogeneity: the key advantages of single-cell analysis

Author

Francois Lamoureux, Marta Tellez-Gabriel, Benjamin Ory, Dominique Heymann, Marie-Françoise Heymann, Laboratorio Hematologia Oncologica y de Transplantes [Barcelona, Spain], Institut Investigacions Biomèdiques (IBB) Sant Pau [Barcelona, Spain]-Hospital de la Santa Creu i Sant Pau, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), This paper was written as a part of a research project which received funding from the Seventh Framework Programme ([FP7/2007-2013]) under grant agreement n 264817—BONE-NET. This work was supported by the Bone Cancer Research Trust (UK, research project number 144681)., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Heymann, Dominique, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID

Subjects
0301 basic medicine, Tumour heterogeneity, circulating tumour cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Review, Biology, Bioinformatics, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, Genetic Heterogeneity, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Single-cell analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, single cells, Neoplasms, Gene expression, Biopsy, medicine, Humans, Epigenetics, Physical and Theoretical Chemistry, Neoplasm Metastasis, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, Organic Chemistry, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Neoplastic Cells, Circulating, Phenotype, 3. Good health, Computer Science Applications, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cancer cell, Cancer research, Single-Cell Analysis, heterogeneity
Abstract

International audience; Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In the last years many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e.: RNA, DNA, protein, epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study with a specific attention to those able to assess heterogeneity at the single cell level.

Published
2016

4. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

Author

Marco Lucarelli, Andrea Fuso, Vincenzina Nicolia, Department of Surgery, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Cellular Biotechnologies and Haematology, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), European Center for Brain Research (CERC)/Santa Lucia Foundation I.R.C.C.S., This paper was supported by funding from the EC 7th Framework Program (FP7/2007–2013) grant no. 278486 'DEVELAGE' and from the Sapienza Università di Roma, Scientific Research Programs 2012 and 2013., European Project: 278486,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,DEVELAGE(2012), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)

Subjects
Adult, Aging, Nutritional Status, Disease, Biology, Alzheimer's Disease, Biochemistry, Epigenesis, Genetic, Endocrinology, Alzheimer Disease, Mental stress, Genetics, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Neurodegeneration, Molecular Biology, Organism, DNA methylation, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Age Factors, food and beverages, Neurodegenerative Diseases, Cell Biology, Epigenome, medicine.disease, 3. Good health, B vitamins, Vitamin B Complex, Gene-Environment Interaction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, epigenetics, neurodegeneration, Alzheimer's disease
Abstract

International audience; Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation.

Published
2015