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Oncogenes, Chromatin and Cell Cycle Control

Director

Bruno Amati

Activities

Dr Amati’s Research Group operates between the European Institute of Oncology and the partner Institution, The Italian Institute of Technology where Dr Amati serves as Director of the Center for Genomic Science of IIT@SEMM

Oncogenic signals induce cell cycle progression and malignant transformation, but concomitantly elicit tumor-suppressive mechanisms (including apoptosis, senescence, and/or DNA Damage Responses), which must be bypassed in order to allow tumor progression, and which constitute the main selective pressure for mutation and/or silencing of tumor suppressor genes. Apoptosis and senescence also determine the therapeutic efficacy of genotoxic treatments (whether chemo- or radio-therapy). Hence, the same genetic lesions and/or epigenetic alterations that allow tumor progression also influence therapeutic responses.

Our group has a long-standing interest in the c-myc oncogene and its product, the Myc protein. Under physiological circumstances, Myc is a central regulator of the cellular responses to extracellular stimuli. When its expression becomes uncontrolled, however, Myc acquires potent oncogenic properties. Myc is a transcription factor: it functions as a heterodimer with a unique partner, Max. The Myc/Max dimer directly or indirectly binds a multitude of target genes, and can either activate or repress transcription.

In general terms, our research aims at explaining the oncogenic activity of Myc, its action on the genome, its effects on cell cycle progression, cell death and differentiation, the tumor suppressor pathways that antagonize it, and their impact on tumor progression and maintenance.

We also use Myc as a paradigm to study the epigenetic organization and regulation of the genome. In particular, we are interested in understanding how specific chromatin environments – or epigenetic states – determine recognition by Myc of its binding sites in the human and mouse genomes, and how Myc further modifies chromatin to regulate gene expression. These studies rely on advanced protocols based on next-generation DNA sequencing technology (ChIP-seq, RNA-seq and others).

  • Publications

    Last 10 years:

      1. Amati B*, Sanchez-Arévalo Lobo VJ
        Myc Degradation: deubiquitinating enzymes enter the dance.
        Nature Cell Biology 9, 729-732 (2007) [news & views]; DOI: 10.1038/ncb0707-729
      1. Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L, Martinato F, Sardella D, Verrecchia A, Bennett S, Confalonieri S, Cesaroni M, Marchesi F, Gasco M, Scanziani E, Capra M, Mai S, Nuciforo P, Crook T, Lough J, Amati B*
        Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response.
        Nature 448, 1063-1067 (2007); DOI: 10.1038/nature06055
      1. Guccione E, Bassi C, Casadio F, Martinato F, Cesaroni M, Schuchlautz H, Lüscher B, Amati B*
        Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive.
        Nature 449, 933-937 (2007); DOI: 10.1038/nature06166
      1. Bonetti P, Davoli T, Sironi C, Amati B, Pelicci PG, Colombo E
        Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma.
        J Cell Biol 182, 19-26 (2008); DOI: 10.1083/jcb.200711040
      1. De Filippis L, Ferrari D, Rota Nodari L, Amati B, Snyder E, Vescovi AL
        Immortalization of human neural stem cells with the c-myc mutant T58A
        PLoS ONE 3, e3310 (2008); DOI: 10.1371/journal.pone.0003310
      1. Martinato F, Cesaroni M, Amati B*, Guccione E
        Analysis of Myc-induced histone modifications on target chromatin.
        PLoS ONE 3, e3650 (2008); DOI: 10.1371/journal.pone.0003650
      1. Smith AP, Verrecchia A, Fagà G, Doni M Martinato F, Guccione E, Amati B*
        A positive role for Myc in TGFb-induced Snail transcription and Epithelial to Mesenchymal Transition.
        Oncogene 28, 422-430 (2009); DOI: 10.1038/onc.2008.395
    1. Bua DJ, Kuo AJ, Cheung P, Liu CL, Migliori V, Espejo A, Casadio F, Bassi C, Amati B, Bedford MT, Guccione E, Gozani O
      Epigenome microarray platform for proteome-wide dissection of chromatin-signaling networks.
      PLoS ONE 4, e6789 (2009); DOI: 10.1371/journal.pone.0006789
      1. Campaner S, Doni M, Hydbring P, Verrecchia A, Bianchi L, Sardella D,  Schleker T, Perna D, Tronnersjö S, Murga M, Fernandez-Capetillo O, Barbacid M,  Larsson LG, Amati B*
        Cdk2 suppresses cellular senescence induced by the myc oncogene.
        Nature Cell Biol. 12, 54-59 (2010); DOI: 10.1038/ncb2004
      1. Pistoni M, Verrecchia A, Doni M, Guccione E, Amati B*
        Chromatin association and regulation of rDNA transcription by the Ras-family protein RasL11a.
         EMBO Journal 29, 1215-1224 (2010);DOI:10.1038/emboj.2010.16
      1. Campaner S, Doni M, Verrechia A, Fagà G, Bianchi L, Amati B*
        Myc, Cdk2 and cellular senescence: old players, new game.
        Cell Cycle, 9, 3655-3661 (2010);DOI: 10.4161/cc.9.18.13049
      1. Müller J, Samans B, van Riggelen J, Fagà G, Peh KNR, Wei CL, Müller H, Amati B, Felsher D, Eilers M
        TGFβ-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas.
        Cell Cycle 9, 4622-4626 (2010);DOI: 10.4161/cc.9.23.14211
      1. Miluzio A, Beugnet A, Grosso S, Brina D, Mancino M, Campaner S, Amati B, de Marco A, Biffo, S
        Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth.
        Cancer Cell, 19, 765-775 (2011);DOI: 10.1016/j.ccr.2011.04.018
      1. Campaner S, Spreafico F, Burgold T, Doni M, Rosato U, Amati B*, Testa G*
        The methyltransferase Setd7 is dispensable for the p53-mediated DNA damage response.
        Mol Cell 43, 681-688 (2011);DOI: 10.1016/j.molcel.2011.08.007
      1. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montaña MF, D' Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O
        Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors.
        Nature Struct & Mol Biol. 18, 1331-1335 (2011); DOI: 10.1038/nsmb.2189.
      1. Migliori V, Muller J, Phalke S, Low D, Bezzi M, Mok W.C, Sahu SK, Gunaratne J, Capasso P, Bassi C, Cecatiello V, De Marco A, Blackstock W, Kuznetsov V, Amati B, Mapelli M, Guccione E
        Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance.
        Nature Struct & Mol Biol. 19, 136-144 (2012);DOI: 10.1016/j.molcel.2011.08.007
      1. Perna D, Fagà G, Verrecchia A, Gorski MM, Barozzi I, Narang V, Khng J, Lim KC, Sung WK, Sanges R, Stupka E, Oskarsson T, Trumpp A, Wei CL, Müller H, Amati B*
        Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts.
        Oncogene 31, 1695-1709 (2012);DOI: 10.1038/onc.2011.359
      1. Beck S. & AACR Cancer Epigenome Task Force (incl. Amati, B.)
        A blueprint for an international cancer epigenome consortium. A report from the AACR Cancer Epigenome Task Force.
        Cancer Res. 72, 6319-6324 (2012);DOI: 10.1158/0008-5472.CAN-12-3658
      1. Campaner S, Amati B
        Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance.
        Cell Div. 7, 6 (2012) [review];DOI: 10.1186/1747-1028-7-6
      1. Sanchez-Arévalo Lobo V.J, Doni M, Verrecchia A, Sanulli S, Piontini A, Bianchi M, Conacci-Sorrell M, Mazzarol M, Peg V, Hernandez Losa J, Ronchi P, Ponzoni M, Eisenman RN, Doglioni C, Amati B*
        Dual regulation of Myc by Abl.
        Oncogene 32, 5261–5271 (2013);DOI: 10.1038/onc.2012.621
      1. Campaner S, Viale A, De Fazio S, Doni M, De Franco F, D'Artista L, Sardella D, Pelicci PG, Amati B
        A non-redundant function of cyclin E1 in Hematopoietic Stem Cells.
        Cell Cycle 12, 3663-3672 (2013);DOI: 10.4161/cc.26584
      1. Sabò A, Amati B*
        Genome recognition by Myc.
        Cold Spring Harb Perspect Biol. 4:a014191 (2014) [review];DOI: 10.1101/cshperspect.a014191
      1. Sabò A, Doni M, Amati B*
        SUMOylation of Myc-family proteins
        PLoS ONE 9, e91072 (2014);DOI: 10.1371/journal.pone.0091072
      1. Almouzni G, Altucci L, Amati B, Ashley N, Baulcombe D, Beaujean N, Bock C, Bongcam-Rudloff E, Bousquet J, Braun S, de Paillerets BB, Bussemakers M, Clarke L, Conesa A, Estivill X, Fazeli A, Grgurevi NA, Gut I, Heijmans BT, Hermouet S, Houwing Duistermaat J, Iacobucci I, Ila J, Kandimalla R, Krauss-Etschmann S, Lasko P, Lehmann S, Lindroth A, Majdi G, Marcotte E, Martinelli G, Martinet N, Meyer E, Miceli C, Mills K, Moreno-Villanueva M, Morvan G, Nickel D, Niesler B, Nowacki M, Nowak J, Ossowski S, Pelizzola M, Pochet R, Poto Nik U, Radwanska M, Raes J, Rattray M, Robinson MD, Roelen B, Sauer S, Schinzer D, Slagboom E, Spector T, Stunnenberg HG, Tiligada E, Torres-Padilla ME, Tsonaka R, Van Soom A, Vidakovi M, Widschwendter M.
        Relationship between genome and epigenome - challenges and requirements for future research.
        BMC Genomics 15, 487 (2014);DOI:  10.1186/1471-2164-15-487
      1. Sabò A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, Morelli MJ, Bora P, Doni M, Verrecchia A, Tonelli C, Fagà G, Bianchi V, Ronchi A, Low D, Müller H, Guccione E, Campaner S, Amati B*
        Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis.
        Nature 511, 488-492 (2014);DOI: 10.1038/nature13537
      1. Pelizzola M*, Morelli MJ, Sabò A, Kress TR, de Pretis S, Amati B*,
        Selective transcriptional regulation by Myc: experimental design and computational analysis of high-throughput sequencing data
        Data in Brief 3, 40-46 (2015);DOI: 10.1016/j.dib.2015.02.003
      1. de Pretis S, Kress TR, Morelli MJ, Melloni GEM, Riva L, Amati, Pelizzola
        INSPEcT: a Computational Tool to Infer mRNA Synthesis, Processing and Degradation Dynamics from RNA- and 4sU-seq Time Course Experiments
        Bioinformatics 31, 2829-2835 (2015);DOI: 10.1093/bioinformatics/btv288
      1. Koh CM, Bezzi M, Low DHP, Ang WX, Teo SX, Gay FPH, Al-Haddawi M, Tan SY, Osato M, Sabò A, Amati B, Wee KB, Guccione E
        MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis
        Nature 523, 96-100 (2015);DOI: 10.1038/nature14351
      1. Tonelli C, Morelli MJ, Bianchi S, Rotta L, Capra T, Sabò A, Campaner S, Amati B*
        Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo
        Oncotarget 6, 24611-24626 (2015); DOI: 10.18632/oncotarget.5232
      1. Kress TR, Sabò A, Amati B*
        Myc: connecting selective transcriptional control to global RNA production
        Nature Reviews Cancer, 15, 593-607 (2015); DOI:10.1038/nrc3984
      1. Kishore K, de Pretis S, Lister R, Morelli MJ, Bianchi V, Amati B, Ecker JR, Pelizzola M
        methylPipe and compEpiTools: a suite of R packages for the integrative analysis of epigenomics data
        BMC Bioinformatics 16, 313 (2015); DOI: 10.1186/s12859-015-0742-6
      1. Tonelli C, Amati B, Morelli MJ
        p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo: Computational analysis of next-generation sequencing data
        Genomics Data 7, 26-31 (2015); DOI:10.1016/j.gdata.2015.11.006.
      1. Marzi M, Ghini F, Cerruti B, De Pretis S, Bonetti P, Giacomelli C, Gorski MM, Kress T, Pellizzola M, Muller H, Amati B, Nicassio F
        Degradation dynamics of microRNAs revealed by a novel pulse-chase approach
        Genome Res. 26, 554-65(2016);DOI: 10.1101/gr.198788.115
      1. D'Artista L, Bisso A, Piontini A, Doni, M, Verrecchia A, Kress TR, Morelli MJ, Del Sal G, Amati B*, Campaner S*
        Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc
        Oncotarget (2016) 7, 21786-98; DOI: 10.18632/oncotarget.7846
      1. Kress TR, Pellanda P, Pellegrinet L, Bianchi V, Nicoli P, Doni M, Recordati C, Bianchi S, Rotta L, Capra T, Ravà M, Verrecchia A, Radaelli E, Littlewood TD, Evan GI and Amati B*
        Identification of Myc-dependent transcriptional programs in oncogene-addicted liver tumors
        Cancer Research 76, 3463-72 (2016);DOI: 10.1158/0008-5472.CAN-16-0316
      1. Bianchi V, Ceol A, Ogier AG, De Pretis S, Galeota E, Kishore K, Bora P, Croci O, Campaner S, Amati B, Morelli MJ and Pelizzola M
        Integrated systems for NGS data management and analysis: open issues and available solutions
        Front. Genet. 7:75 (2016); DOI: 10.3389/fgene.2016.00075
      1. Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, Rajkowska K, Gaweda-Walerych K, Ingallina E, Tonelli C, Morelli MJ, Amato A, Eterno V, Zambelli A, Rosato A, Amati B, Wisniewski JR and Del Sal G
        Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer
        Nature Cell Biology 18, 897-909; DOI:10.1038/ncb3380
      1. BagislarS, Sabò A, Kress T, Doni M, Nicoli P, Campaner S, Amati B*.
      2. Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis.
      3. Oncotarget 7, 66398-415 (2016); DOI: 10.18632/oncotarget.11719
      1. D' Andrea A, Gritti I, Nicoli P, Giorgio M, Doni M, Conti A, Bianchi V, Casoli L, Sabò A, Mironov A, Beznoussenko GV, Amati B*.
      2. The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas.
      3. Oncotarget 7, 72415-30 (2016); DOI: 10.18632/oncotarget.11719
      1. Ravà M, D' Andrea A, Doni M, Kress TR, Ostuni R, Bianchi V, Morelli, MJ, Collino A, Ghisletti S, Nicoli P, Recordati C, Iascone M, Sonzogni A, D'Antiga L, Shukla R, Faulkner GJ, Natoli G, Campaner S, Amati B*.
      2. Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18.
      3. Hepatology 65, 1708-1719 (2017); DOI: 10.1002/hep.28942
      1. Argemí J, Kress TR, Chang HC, Bértolo C, Ferrero R, Moreno H, González-Aparicio M, Hernández-Alcoceba R, Segura V, Uriarte I, Guembe L, Avila MA, Amati B, Prieto J, Aragón T.
      2. X-box Binding Protein 1 Regulates Unfolded Protein, Acute-phase, and DNA Damage Responses During Regeneration of Mouse Liver.
      3. Gastroenterology 152, 1203–1216 (2017). DOI: 10.1053/j.gastro.2016.12.040
      1. Tonelli C, Morelli MJ, Sabò A, Rotta L, Capra T, Bianchi S, Campaner S, Amati B*.
      2. Genome-wide analysis of tumor suppressive programs during p53-induced regression in Myc-driven lymphomas.
      3. Oncogene 36, 2921-2929 (2017); DOI: 10.1038/onc.2016.443
    2. Piccolo V, Curina1 A, Genua M, Ghisletti S, Simonatto M, Sabò A, Amati B, Ostuni R, Natoli G.
      1. Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross talks.
      2. Nature Immunology 18, 530-540 (2017), DOI:10.1038/ni.3710
    3. Parodi ACL, Sangalli LM, Vantini S, Amati B, Secchi P, Morelli MJ.
        1. FunChIP: an R/Bioconductor package for functional classification of ChIP-seq shapes.
        2. Bioinformatics 33, 2570-2572 (2017); DOI: 10.1093/bioinformatics/btx201
    4. De Pretis S, Kress TR, Morelli MJ, Sabò A, Locarno C, Verrecchia A, Doni M, Campaner S, Amati B, Pelizzola M.         
          1. Integrative analysis of RNA Polymerase II and transcriptional dynamics upon MYC activation.
          2. Genome Res. Advance Online Publication (2017); DOI: 10.1101/gr.226035.117

     

    (* Corresponding Author)

UN PICCOLO GESTO E' PER NOI UN GRANDE AIUTO

PARTNERSHIP

Università degli Studi di Milano Ecancer Medical Science IFOM-IEO Campus

CREDITS

Ministero della Salute Joint Commission International Breastcertification bollinirosa

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IRCCS - ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO

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