Cherubini Alessandro, PhD student cherubini@ingm.org
Fasciani Alessandra, Graduate Fellow fasciani@ingm.org
Malagoli Zagliazucchi Guidantonio, PhD, malagoli@ingm.org
Poli Vittoria, PhD student poli@ingm.org

Scientific Background

Stem cells have the unique ability to generate both self-renewing and differentiating daughter cells through asymmetric cell division. In both embryonic and adult stem cells the balance between self-renewal and lineage commitment is tightly modulated by integrating environmental signals with intrinsic transcriptional regulatory networks. The extracellular signaling switch that characterizes the transition from self-renewal to differentiation induces a dramatic change in gene expression patterns that eventually will determine the cell-specific epigenetic state. How do cell translate the temporary environmental signals into a stable and persistent gene expression state? The general view is that extrinsic signalling leads to an intracellular signal transduction cascade that is ultimately “translated” by transcription factors into changes of the chromatin state. The main focus of our newly established team is to investigate epigenetic mechanisms that dictate the establishment and the maintenance of stem cell identity. We aim to dissect the molecular mechanisms through which transcription factors mediate the epigenetic responses to environmental signalling in Embryonic and Cancer Stem Cells. In fact, a tight control of those determinants that dictate the decision to retain or to exit pluripotency permits the maintenance proper tissue homeostasis without which abnormal cell population states such as Cancer Stem Cell may be fostered. We intent to tackle this biological question using a multidisciplinary approach that, by combining dynamic single cell tracking strategy with the epigenetic profiling of stem cells should allow us to determine the network of combinatorial epigenetic modifications that establish a stem cell-like epigenetic state.
We are currently focusing our attention on the molecular mechanisms through which the transcription factor Myc influences global chromatin structure in ESC using biochemical, molecular and genetic approaches. In particular we are determining the contribution of Myc in integrating environmental signals with the core regulatory transcription network.
On the same line, we are also investigating whether Myc plays a key role in determining the formation of CSC by favoring the establishment of a stem cell-like epigenetic signature. We are focusing on the dynamic epigenetic changes occurring at defined loci in primary mammary epithelial cells going through a Myc-induced reprogramming towards a primitive stem cell-like state.
In the same cellular context, we are also investigating the molecular mechanisms through which the activation of the Wnt/β-catenin pathway promotes the establishment and the maintenance of the mammary CSC. In particular, we will focus in analyzing the downstream effects of β-catenin activation at the chromatin level including the expression signature and the epigenetic state of the CSC.

Ongoing Projects

  1. Role of Myc in determining the epigenetic state of Embryonic Stem Cells.
  2. Epigenetic mechanisms controlling the establishment of Cancer Stem Cells.
  3. Wnt/β-catenin signaling in stem cells.

Recent Publications

A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity
Fagnocchi L, Cherubini A, Hatsuda H, Fasciani A, Mazzoleni S, Poli V, Berno V, Rossi RL, Reinbold R, Endele M, Schroeder T, Rocchigiani M, Szkarłat Ż, Oliviero S, Dalton S, Zippo A.
Nat Commun. 2016 Jun 15;7:11903.

Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes
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
J Cell Biol. 2015 Oct 13;6:527. doi: 10.3389/fimmu.2015.00527. eCollection 2015. Review.

The characterization of a novel monoclonal antibody against CD93 unveils a new antiangiogenic target.
Orlandini M, Galvagni F, Bardelli M, Rocchigiani M, Lentucci C, Anselmi F, Zippo A, Bini L, Oliviero S.
Oncotarget. 2014 May 15;5(9):2750-60.

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

Myc regulates the transcription of PRC2 to control the expression of developmental genes in embryonic stem cells
Neri F, Zippo A, Krepelova A, Cherubini A, Rocchigiani M, and Oliviero S.
Mol Cell Biol. 2012 Feb;32(4):840-51

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

PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation
Zippo A, De Robertis A, Serafini R, Oliviero S.
Nat Cell Biol. 2007 Aug;9(8):932-44

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