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Overview | Research directions | Group members | Collaborations | Selected Publications

Overview

Epigenetics allows cells to adapt to environmental alterations, causing heritable yet reversible changes of the cellular state. Perturbations of the epigenetic machinery are often responsible for diseases. The main focus of our team is to investigate how epigenetic changes could impact on stem cells, both in physiological and pathological settings. We aim to dissect the molecular mechanisms through which transcription factors mediate the epigenetic responses to environmental signals in stem cells. We intent to tackle this biological question using a multidisciplinary approach that, by combining dynamic single cell tracking strategy with the epigenetic profiling of cells, should allow to determine the network of combinatorial epigenetic modifications that establish a stem cell-like epigenetic state. On the same line we are also interested in understanding the contribution of oncogene-induced epigenetic reprogramming to tumor progression and metastasis formation.

Research directions

MYC-driven epigenetic memory in stem cell maitenance: The pluripotent state of embryonic stem cells is stabilized by alternative stimuli and factors. Among these we recently discovered that the prolonged activation of the MYC transcription factor is sufficient to establish an epigenetic memory, which sustains ESCs identity. By using an integrative approach we aim to decipher the transcriptional and epigenetic foundation of the MYC-induced epigenetic memory in ESCs.

Role of MYC as tumor reprogramming factor: The role of MYC in reprogramming of somatic cells towards pluripotent stem cells is well established but is mechanism of action is poorly defined. We are investigating whehter MYC could acts as an oncogenic reprogramming factor by inducing cell plasticity that predisposes mammary luminal epithelial cells to acquire basal/stem cell-like properties, giving rise to tumor initiating cells endowed with long-term tumorigenic capacity and metastatic potential. Specifically, we are defining the contribution of this oncogene to induce an epigenetic switch that re-direct differentiated cells towards the activation of a stem cell-like transcriptional program.

Deciphering the role of epigenetic reprogramming in driving cell plasticity during tumor progression and metastasis: Cancer genomics showed that tumor progression to metastasis formation is poorly supported by further genetic alterations, implying that the adaptation capacity of disseminating tumor cells to foreign microenvironments could rely on reversible epigenetic alterations. Using pre-clinical model of basal-like breast cancer, we are investigating the contibution of epigenetic reprogramming to cancer-driven cell plasticity.

Epigenetic alterations in rare genetic disorders: Many inherited disorders result from mutations in the genes encoding various components of the epigenetic machinery. Among others, we are investigating the pathological role of the mutated MLL4 in the aetiology of the Kabuki Syndrome, a multiple congenital anomaly disorder lacking therapeutic options. By developing an in vitro disease model system, we are establishing whether the pathogenesis of this disorder depends on the MLL4-associatd epigenetic alterations.

Group members

  • Alessio Zippo, PI
  • Luca Fagnocchi, postdoctoral fellow
  • Vittoria Poli, postdoctoral fellow
  • Alessandra Fasciani, PhD student
  • Daniela Michelatti, PhD student
  • Francesco Corazza, Master student
  • Silvia Rizzato, undergraduate student

We are always interested in highly motivated candidates from the undergraduate student to postdoc level. Please contact directly the PI Alessio Zippo.

Collaborations

  • Prof. Timm Schroeder (ETH Zurich, Switzerland)
  • Prof. Steven Dalton (The University of Georgia, Athens, Georgia USA)
  • Prof. Giorgio Stassi (Università degli Studi di Palermo, Italy)
  • Prof. Vania Broccoli (San Raffaele Scientific Institute, Italy)
  • Prof. Andrea Bassi (Politecnico di Milano, Italy)
  • Prof. Nicola Aceto (University of Basel, Switzerland)

Selected publications

Fagnocchi L, Poli V, Zippo A, Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity. Cell Mol Life Sci. 2018 Apr 24

Poli V, Fagnocchi L, Fasciani A, Cherubini A, Mazzoleni S, Ferrillo S, Miluzio A, Gaudioso G, Vaira V, Turdo A, Giaggianesi M, Chinnici A, Lipari E, Bicciato S, Bosari S, Todaro M, Zippo A, MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state.
Nat Commun. 2018 Mar 9;9(1):1024

Bodega B, Marasca F, Ranzani V, Cherubini A, Della Valle F, Neguembor MV, Wassef M, Zippo A, Lanzuolo C, Pagani M, Orlando V., A cytosolic Ezh1 isoform modulates a PRC2-Ezh1 epigenetic adaptive response in potmitotic cells.
Nat Struct Mol Biol. 2017 May; 24(5):444-452

Alessandro Cherubini and Alessio Zippo, Fluorescence Resonance Energy Transfer microscopy for measuring chromatin complex structure and dynamics.
Methods in Molecular Biology, 2016

Luca Fagnocchi, Mazzoleni Stefania and Alessio Zippo, Integration of Signalling pathways with the epigenetic machinery in the maintenance of stem cells.
Stem Cell International, March 2016

Elisa Cesarini, Chiara Mozzetta, Fabrizia Marullo, Francesco Gregoretti, Annagiusi Gargiulo, Marta Columbaro, Alice Cortesi, Laura Antonelli, Simona Di Pelino, Stefano Squarzoni, Daniela Palacios, Alessio Zippo, Beatrice Bodega, Gennaro Oliva and Chiara Lanzuolo, Lamin A/C sustains PcG proteins architecture maintaining repression of target genes.
Journal of Cell Biology 2015 Nov 9;211(3):533-51

Maurizio Orlandini, Federico Galvagni, Monia Bardelli, Marina Rocchigiani, Francesca Anselmi, Luca Bini, Alessio Zippo and Salvatore Oliviero, The characterization of a novel monoclonal antibody against CD93 unveils a new antiangiogenic target.
Oncotarget, 2014 May 15;5(9):2750-60

Evellin S, Galvagni F, Zippo A, Neri F, Orlandini M, Incarnato D, Dettori D, Neubauer S, Kessler H, Wagner EF, Oliviero S, FOSL1 controls the assembly of endothelial cells into capillary tubes by direct repression of αv and β3 integrin transcription.
Mol Cell Biol. 2013 Mar;33(6):1198-209

Francesco Neri, Alessio Zippo, Anna Krepelova, Alessandro Cherubini, Marina Rocchigiani, and Salvatore Oliviero, MYC regulates the transcription of PRC2 to control the expression of developmental genes in embryonic stem cells.
Mol Cell Biol. 2012 Feb;32(4):840-5

Zippo A, Serafini R, Rocchigiani M, Pennacchini S, Krepelova A, Oliviero S, Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation.
Cell. 2009 Sep 18; 138(6):1122-36

Zippo A, De Robertis A, Serafini R, Oliviero S, PIM1-dependent phosphorylation of Histone H3 at Serine 10 is required for the transcriptional activation of MYC-target genes.
Nat Cell Biol. 2007 Aug; 9(8):932-44