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Transcriptional control of inflammation and Cancer

Activities

The main objective of the lab is to understand mechanisms that control the expression of inflammatory genes.

Inflammation is a basic response to environmental and endogenous danger signals (such as microbes and cell debris, respectively) that serves an essential homeostatic and therefore beneficial role. At the same time, excessive or unresolved inflammation promotes the development of many disorders, ranging from autoimmune diseases to cancer.

Inflammation entails the induction (and repression) of hundreds of genes whose products contribute to different aspects of the response, such as the recruitment of leukocytes, changes in vascular permeability, the activation of anti-bacterial responses, and eventually the induction of a repair response leading to reconstitution of tissue integrity. An in-depth understanding of such mechanisms may provide the molecular basis for therapeutic targeting of selected transcriptional events. To achieve these objectives, standard biochemical approaches to transcription are integrated with genomics, computational approaches, physics and in vivo studies.

  • Research projects

    Most of the research tackled by the laboratory relates to one of the most important cell types involved in inflammation, namely macrophages. Macrophages are highly specialized cells widely distributed in tissues and active both as immune effectors and as housekeeping phagocytes responsible for maintenance of tissue integrity. Macrophages display a striking heterogeneity that reflects a complex interplay between different micro-environmental signals provided by various tissues (as well as by microbial and endogenous stress signals), and a robust differentiation program that determines macrophage identity. The main objective of the research activity in this unit is to understand how macrophage identity, functional specialization and plasticity are controlled by their specialized genomic organization, which is encoded in mammalian genomes, enforced by specific transcription factors, and modulated by the microenvironment. Within this area we provided the first genome-wide characterization of the genomic regulatory elements (enhancers) controlling inflammatory gene expression in macrophages. We determined a general organizational principle of these enhancers, which consists in the combination of binding sites for ubiquitous, stimulus-responsive transcription factors and binding sites for constitutive cell type-restricted and lineage-determining transcription factors. Specifically, we have found that in macrophages genomic regulatory elements that control inflammatory gene expression contain two minimal elements, namely a binding site for one or more of the transcription factors activated in response to stimulation (such as NF-kB and AP-1), and a binding site for the major transcription factor controlling macrophage specification, Pu.1. This combination allows creating a cell type-specific context within which transcription of inflammatory genes is regulated, thus explaining variability among cell types in the inflammatory gene expression program induced by identical stimuli. Interestingly, part of the enhancers controlling inflammatory gene expression were found to undergo transcription, which may be instrumental to the maintenance of an open chromatin configuration and/or to the production of non-coding RNAs that signal downstream transcriptional events.

    Ongoing research in the lab is mainly focused on the characterization of the impact of different environmental stimuli on the functional organization of macrophage genome using both in vitro models and ex-vivo analyses on macrophages obtained from tissues and primary tumors.

    As part of this effort we are characterizing the role of a panel of chromatin modifying enzymes, which represent potential drug targets, in the control of inflammatory responses. In this area we have reported a few years ago the first description of a histone demethylase involved in inflammatory gene expression. More recent work allowed us to identify a required role of specific histone methyltransferases and histone deacetylases in the control of macrophage responsiveness to inflammatory stimuli.

  • Publications

    • Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma (Shukla R, Upton K, Muñoz-Lopez M, Gerhardt D, Fisher M, Nguyen T, Brennan T, Baillie T, Collino A, Ghisletti S, Sinha S, Iannelli F, Radaelli F, Dos Santos A, Rapoud D, Guettier C, Samuel D, Natoli G, Carninci P, Ciccarelli F, Garcia-Perez JC, Faivre J, Faulkner G.) Cell in press (2013)
    • Latent enhancers activated by stimulation in differentiated cells (Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G.) Cell 152: 157-71 (2013).
    • The H3K27 Demethylase JMJD3 Is Required for Maintenance of the Embryonic Respiratory Neuronal Network, Neonatal Breathing, and Survival (Burgold T, Voituron N, Caganova M, Tripathi PP, Menuet C, Tusi BK, Spreafico F, Bvengut M, Gestreau C, Buontempo S, Simeone A, Kruidenier L, Natoli G, Casola S, Hilaire G, Testa G.) Cell Reports 2:1244-58 (2012).
    • Hdac3 requirement for the inflammatory gene expression program (X. Chen, I. Barozzi, A. Termanini, E. Prosperini, A. Recchiuti, J. Dalli, F. Mietton, G. Matteoli, S. Hiebert, G. Natoli) Proc. Natl. Acad. Sci. USA 109:E2865-74 (2012).
    • Noncoding transcription at enhancers: general principles and functional models (G. Natoli and J.C. Andrau) Annual Review of Genetics 46:1-19 (2012).

     

    All publications

  • Funding

    • European Research Council (ERC Advanced grant)
    • Italian Association for Research on Cancer (A.I.R.C.)
    • Association for International Cancer Research (AICR-UK)
    • EC-FP7 Large Scale Integrating Project MODHEP
    • MIUR Italian Ministry for University and Research (FIRB project)

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

© 2013 Istituto Europeo di Oncologia - via Ripamonti 435 Milano - P.I. 08691440153

IRCCS - ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO

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