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.
1. 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..
2. 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.
3. Solving 3D chromatin organization and its mechanical properties in health and diseases
Chromatin is organized in biomolecular condensates that compartmentalized the genome function and control gene expression. The herein program aims to solve chromatin domains by super-resolution imaging and optogenetic-based tools, to determine the contribution of 3D chromatin organization and nuclear architecture to the onset and progression of breast cancer. By using cutting-edge technologies, we are developing new approaches to define and solve chromatin domains to investigate their function in promoting cancer cell plasticity.
4. 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.
- Alessio Zippo, PI
- Sven Beyes, postdoctoral fellow
- Vittoria Poli, postdoctoral fellow
- Sara Lago, postdoctoral fellow
- Daniela Michelatti, PhD student
- Sarah D'Annunzio, PhD student
- Chiara Bernardis, post-graduate student
- Elisa Facen, post-graduate student
- Federica Busi, post-graduate student
- Enrico Sebastiani, undergraduate student
We are currently looking for highly motivated candidates for:
- PhD position to investigate epigenetic reprogramming of enhancers during breast cancer progression.
- Post-doc fellowship in single-molecule microscopy and quantitative bioimaging to solve chromatin compartmentalization in cancer cells
If interested, please contact directly the PI for detailed informations
- 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. Mark Neil (Imperial College, UK)
- Prof. Vania Broccoli (San Raffaele Scientific Institute, Italy)
- Prof. Andrea Bassi (Politecnico di Milano, Italy)
- Prof. Giancarlo Ruocco (University of Rome, Italy)
Aiello G, Ballabio C, Ruggeri R, Fagnocchi L, Ruggeri R, Ilaria Morassut I, Caron D, Garilli F, Gianno F, Giangaspero F, Piazza S, Romanel A, Zippo A and Tiberi L. Truncated BRPF1 cooperates with Smoothened to promote adult Shh medulloblastoma. Cell Reports, 2019, in press
Sessa A, Fagnocchi L, Mastrototaro G, Massimino L, Zaghi M, Indrigo M, Cattaneo S, Martini D, Gabellini C, Pucci C, Di Pelino2 S, Taverna S, Andreazzoli M, Zippo A,* and Broccoli V,* SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring. Neuron 2019 Oct 23;104(2):271-289.e13* Co-senior Authors.
Narayanan A, Gagliardi F, Gallotti AL, Mazzoleni S, Cominelli M, Fagnocchi L, Pala M, Piras IS, Zordan P, Moretta N, Tratta E, Brugnara G, Altabella L, Bozzuto G, Gorombei P, Molinari A, Padua RA, Bulfone A, Politi LS, Falini A, Castellano A, Mortini P, Zippo A, Poliani PL, Galli R. The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1. Cell Death Differ. 2018 Dec 11.
Poli V , Fagnocchi L and Zippo A. Tumorigenic Cell Reprogramming and Cancer Plasticity: Interplay between Signaling, Microenvironment, and Epigenetics. Stem Cell Int. 2018 May 2;2018:4598195.
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
Cherubini A and Zippo A. Fluorescence Resonance Energy Transfer microscopy for measuring chromatin complex structure and dynamics. Methods in Molecular Biology, 2016
Fagnocchi L, Mazzoleni S and Zippo A. Integration of Signalling pathways with the epigenetic machinery in the maintenance of stem cells. Stem Cell International, March 2016.
Cesarini E, Mozzetta C, Marullo F, Gregoretti F, Gargiulo A, Columbaro M, Cortesi A, Antonelli L, Di PelinoS, Squarzoni S, Palacios D, Zippo A, Beatrice Bodega B, Oliva G and Lanzuolo C. Lamin A/C sustains PcG proteins architecture maintaining repression of target genes. Journal of Cell Biology 2015 Nov 9;211(3):533-51
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 av and b3 integrin transcription. Mol Cell Biol. 2013 Mar;33(6):1198-209.
Neri F, Zippo A, Krepelova A, Cherubini A, Rocchigiani M, and Oliviero S. 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.