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Home » ... » Epigenetic mechanisms in stem cell differentiation and oncogenesis Unit

Epigenetic mechanisms in stem cell differentiation and oncogenesis

Director

Diego Pasini

  • +39 02.94375.139
  • +39 02.94375.990

Activities

Organisms’ development and tissues homeostasis is achieved by a precise control of the fate of differentiating cells. Such regulation is influenced by several cell autonomous and non-autonomous stimuli that are translated into the establishment of specific transcription programs allowing correct fate determination. Establishment and maintenance of such transcription programs involve several different mechanisms that, by acting at a genetic (i.e., DNA sequence recognition by specific DNA binding transcription factors) and at an epigenetic level (i.e., DNA sequence independent mechanisms of transcriptional regulation), resolve the complex three-dimensional structure of chromatin to set up proper transcriptional information. The latter activity involves different enzymes and adaptor proteins that, by remodeling chromatin structure through nucleosome sliding, eviction, histone post translation modifications and DNA methylation, contribute to establish correct transcription. The bypass of cellular identity is a common feature of all human cancers and several mechanisms involved in determining normal cell identity are also essential for tumors development. This also includes the enzymatic activities that are involved in “placing” and “removing” chromatin modifications which are frequent targets of genomic alterations in a large variety of human tumors (i.e. mutations, deletions, translocations and amplifications) that strongly suggests a selective pressure, during cancer development, for altering the proper epigenetic control of normal cells. Thus, the characterization of the molecular mechanisms underling these activities in normal and pathological contexts as well as studying their role in different neoplastic environments, will help not only to better comprehend the molecular basis of cancer development, maintenance and evolution, but also to highlight novel potential pathways that can be pursued for therapy and prognosis.

EXTERNAL LINKS:
 Research Gate: http://www.researchgate.net/profile/Diego_Pasini
OCRID ID: http://orcid.org/0000-0002-9879-6486
ResercherID: http://www.researcherid.com/rid/J-9674-2012

  • Research projects

    Ongoing research activities
    The work of our laboratory focuses its attention on different chromatin modifying activities that are potentially implicated in tumor development. To achieve this, we take advantage of biochemical, cell culture and mouse genetic approaches in order to characterize the role and the molecular mechanisms behind different chromatin modifying activities in normal cellular differentiation and in different contexts of neoplastic transformation. This work can be summarized in the following lines of research.

    Regulation of cell proliferation by chromatin modifiers.
    The mechanisms by which different chromatin modifiers can control cellular proliferation are diverse. Among these, the connection between chromatin modifications and cell proliferation remains in large part poorly understood. This line of research focuses its attention on the activity of Polycomb group proteins (PcG), frequent targets of deregulation in different tumors. Our goal is to study the role of PcGs in regulating normal and cancer cells proliferation as well as to characterize the mechanisms controlled by these activities in proliferating cells. We combine cell culture and in vivo studies taking advantage of mouse genetics in order to elucidate the relevance of PcG inhibition for cancer treatment and to characterize the mechanisms triggered by the loss of PcG activity in normal and cancer cells. Mechanisms of epigenetic control in multi-protein complexes
    Most, if not all, chromatin modifying activities are found associated in large multiprotein complexes. This line of research uses biochemical approaches combined to analyses with mass spectrometry to characterize the diverse composition of protein complexes associated to chromatin in different cellular contexts. For example, this approach allows to study the composition of different chromatin remodeling complexes during normal cell differentiation or to characterize how oncogenic stimuli can alter the structure and activity of specific chromatin modifiers. All together, this approach allows to discover novel functional epigenetic interactions and to characterize how the activity of specific chromatin modifying complexes can be modulated to regulate cell fate in normal and neoplastic conditions.

    Role of Histone and DNA Modifications in transcriptional control and genomic integrity.
    Although a large number of different histone and DNA modifications have been identified in the last two decades, they role in controlling transcriptional processes and genomic integrity still requires a lot of effort for a full comprehension. This part of the work of my laboratory combines next-generation sequencing (NGS), mouse genetic and mass spectrometry approaches to characterize the role of different histone and DNA modifications in regulating chromatin dynamics and gene transcription.

  • Publications

      • Ferrari KJ, Lavarone E, Pasini D. The Dual Role of EPOP and Elongin BC in Controlling Transcriptional Activity. Mol Cell. 2016 Nov 17;64(4):637-638. doi: 10.1016/j.molcel.2016.11.009.
    • Chiacchiera F, Pasini D. Control of adult intestinal identity by the Polycomb repressive machinery. Cell Cycle. 2016 Nov 15:1-2. Epub ahead of print
    • Rossi A, Ferrari KJ, Piunti A, Jammula S, Chiacchiera F, Mazzarella L, Scelfo A, Pelicci PG and Pasini D. Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice. Science Advances. 2016.
    • Jammula S. and Pasini D. EpiMINE, a computational program for mining epigenomic data. Epigenetics and Chromatin. 2016
    • Chiacchiera F, Rossi A, Jammula S, Zanotti M. and Pasini D. PRC2 preserves intestinal progenitors and restricts secretory lineage commitment.EMBO J. 2016.
    • Pasini, D*. and Di Croce*, L. Emerging roles for Polycomb proteins in cancer. Current Opinion in Genetics & Development. 2016.
    • Lenti, E. Farinello, D., Yokoyama, K.K. Penkov, D., Castagnaro, L., Lavorgna, G., Wuputra, K., Sandell, L.L., Butler Tjaden, N.N., Bernassola, F., Caridi, N., De Antoni, A., Wagner, M., Kozinc, K., Niederreither, K., Blasi, F., Pasini, D., Majdic, G., Tonon, G., Trainor, P.A. and Brendolan A. TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development. Journal of Clinical Investigation. 2016.
    • Chiacchiera, F., Rossi, A., Jammula, S., Piunti A., Scelfo, A., Ordóñez-Morán, P., Huelsken, J., Koseki, H. and Pasini, D. Polycomb Complex PRC1 Preserves Intestinal Stem Cell Identity by Sustaining Wnt/ß Catenin Transcriptional Activity. Cell Stem Cell. 2016.
    • Pasini, D. Mapping the Function of Polycomb Proteins. Methods Mol Biol. 2016.
    • Scelfo, A., Piunti, A. and Pasini, D. The controversial role of the Polycomb group proteins in transcription and cancer: how much do we not understand Polycomb proteins?Febs J. 2015
    • Orfanelli, U., Jachetti, E., Chiacchiera, F., Grioni, M., Brambilla, P., Briganti, A., Freschi, M., Martinelli-Boneschi, F., Doglioni, C., Montorsi, F., Bellone, M., Casari, G., Pasini, D. and Lavorgna, G. Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene. 2015
    • Lavorgna, G.C., F. Briganti, A. Montorsi, F. Pasini, D. Salonia, A. Expression-profiling of apoptosis induced by ablation of the long ncRNA TRPM2-AS in prostate cancer cell.Genomics Data. 2015
    • Piunti, A., Rossi, A., Cerutti, A., Albert, M., Jammula, S., Scelfo, A., Cedrone, L., Fragola, G., Olsson, L., Koseki, H., Testa, G., Casola, S., Helin, K., d'Adda di Fagagna, F. and Pasini, D. Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication.Nat Commun. 2014
    • Ferrari, K.J., Scelfo, A., Jammula, S., Cuomo, A., Barozzi, I., Stutzer, A., Fischle, W., Bonaldi, T. and Pasini, D. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Mol Cell. 2014
    • Bartocci, C., Diedrich, J.K., Ouzounov, I., Li, J., Piunti, A., Pasini, D., Yates, J.R., 3rd and Lazzerini Denchi, E. Isolation of chromatin from dysfunctional telomeres reveals an important role for Ring1b in NHEJ-mediated chromosome fusions. Cell Rep. 2014
    • Vella, P., Scelfo, A., Jammula, S., Chiacchiera, F., Williams, K., Cuomo, A., Roberto, A., Christensen, J., Bonaldi, T., Helin, K. and Pasini, D. Tet proteins connect the O-linked Nacetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell. 2013
    • Jung, H.R., Sidoli, S., Haldbo, S., Sprenger, R.R., Schwammle, V., Pasini, D., Helin, K. and Jensen, O.N. Precision mapping of coexisting modifications in histone H3 tails from embryonic stem cells by ETD-MS/MS. Anal Chem. 2013
    • Ferrari, K.J. and Pasini, D. Regulation and function of DNA and histone methylations. Curr Pharm Des. 2013
    • Chiacchiera, F., Piunti, A. and Pasini, D. Epigenetic methylations and their connections with metabolism.Cell Mol Life Sci. 2013
    • Vella, P., Barozzi, I., Cuomo, A., Bonaldi, T. and Pasini, D. Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells. Nucleic Acids Res. 2012
    • Stojic, L., Jasencakova, Z., Prezioso, C., Stutzer, A., Bodega, B., Pasini, D., Klingberg, R., Mozzetta, C., Margueron, R., Puri, P.L., Schwarzer, D., Helin, K., Fischle, W. and Orlando, V. Chromatin regulated interchange between polycomb repressive complex 2 (PRC2)-Ezh2 and PRC2- Ezh1 complexes controls myogenin activation in skeletal muscle cells. Epigenetics Chromatin. 2011
    • Piunti, A. and Pasini, D. Epigenetic factors in cancer development: polycomb group proteins.Future Oncol. 2011
    • Pasini, D., Malatesta, M., Jung, H.R., Walfridsson, J., Willer, A., Olsson, L., Skotte, J., Wutz, A., Porse, B., Jensen, O.N. and Helin, K. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes.Nucleic Acids Res. 2010
    • Pasini, D., Cloos, P.A., Walfridsson, J., Olsson, L., Bukowski, J.P., Johansen, J.V., Bak, M., Tommerup, N., Rappsilber, J. and Helin, K. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature. 2010
    • Leeb, M., Pasini, D., Novatchkova, M., Jaritz, M., Helin, K. and Wutz, A. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 2010
    • Jung, H.R., Pasini, D., Helin, K. and Jensen, O.N. Quantitative mass spectrometry of histones H3.2 and H3.3 in Suz12-deficient mouse embryonic stem cells reveals distinct, dynamic post-translational modifications at Lys-27 and Lys-36. Mol Cell Proteomics. 2010
    • Riising, E.M., Boggio, R., Chiocca, S., Helin, K. and Pasini, D. The polycomb repressive complex 2 is a potential target of SUMO modifications.PLoS One. 2008
    • Pasini, D., Hansen, K.H., Christensen, J., Agger, K., Cloos, P.A. and Helin, K. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev. 2008
    • Pasini, D., Bracken, A.P., Agger, K., Christensen, J., Hansen, K., Cloos, P.A. and Helin, K. Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harb Symp Quant Biol. 2008
    • Lindroth, A.M., Park, Y.J., McLean, C.M., Dokshin, G.A., Persson, J.M., Herman, H., Pasini, D., Miro, X., Donohoe, M.E., Lee, J.T., Helin, K. and Soloway, P.D. Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus.PLoS Genet. 2008
    • Herranz, N., Pasini, D., Diaz, V.M., Franci, C., Gutierrez, A., Dave, N., Escriva, M., Hernandez- Munoz, I., Di Croce, L., Helin, K., Garcia de Herreros, A. and Peiro, S. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008
    • Hansen, K.H., Bracken, A.P., Pasini, D., Dietrich, N., Gehani, S.S., Monrad, A., Rappsilber, J., Lerdrup,  M. and Helin, K. A model for transmission of the H3K27me3 epigenetic mark.Nat Cell Biol. 2008
    • Villa, R., Pasini, D., Gutierrez, A., Morey, L., Occhionorelli, M., Vire, E., Nomdedeu, J.F., Jenuwein, T., Pelicci, P.G., Minucci, S., Fuks, F., Helin, K. and Di Croce, L. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia.Cancer Cell. 2007
    • Pasini, D., Bracken, A.P., Hansen, J.B., Capillo, M. and Helin, K. The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol. 2007
    • Christensen, J., Agger, K., Cloos, P.A., Pasini, D., Rose, S., Sennels, L., Rappsilber, J., Hansen, K.H., Salcini, A.E. and Helin, K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007
    • Bracken, A.P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Monch, K., Minucci, S., Porse, B.T., Marine, J.C., Hansen, K.H. and Helin, K. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007
    • Agger, K., Cloos, P.A., Christensen, J., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A.E. and Helin, K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007
    • Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. and Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.Genes Dev. 2006
    • Lazzerini Denchi, E., Attwooll, C., Pasini, D. and Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol Cell Biol. 2005
    • Pasini, D., Bracken, A.P., Jensen, M.R., Lazzerini Denchi, E. and Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. Embo J. 2004
    • Pasini, D., Bracken, A.P. and Helin, K. Polycomb group proteins in cell cycle progression and cancer. Cell Cycle. 2004
    • Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., Helin, K., Pelicci, P.G., Jochemsen, A.G. and Marine, J.C. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol. 2004
    • Gao, G., Bracken, A.P., Burkard, K., Pasini, D., Classon, M., Attwooll, C., Sagara, M., Imai, T., Helin, K. and Zhao, J. NPAT expression is regulated by E2F and is essential for cell cycle progression.Mol Cell Biol. 2003
    • Bracken, A.P*., Pasini, D*., Capra, M., Prosperini, E., Colli, E. and Helin, K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. Embo J. 2003

    *equal contribution

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

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