Transcriptional control in inflammation and cancer

The research activity in our laboratory is focused on understanding the molecular control of inflammatory gene expression and on the epigenetic mechanisms linking chronic inflammation to cancer development.

Inflammatory responses are complex biological reactions activated by microbial and non-microbial triggers, and impacting on a broad variety of normal and pathological conditions. Inflammation underlies processes as different as the efficient elimination of invading microbes; abnormal acute responses leading to septic shock; and tissue-destructive diseases like rheumatoid arthritis. An inflammatory infiltrate is also an integral component of tumors and is believed to contribute to some tumor properties like formation of new blood vessels and tissue invasion. Both acute and chronic inflammation involves dynamic and coordinated changes in expression of hundreds of genes, which reflects specific functions of different gene products during subsequent stages of the response. Myeloid cells and macrophages in particular, are crucial mediators of inflammation. Macrophages are abundantly and broadly represented in peripheral tissues and act both as effector cells of the immune system, endowed with a broad microbial recognition capacity, and as housekeeping phagocytes constantly working to remove debris and maintain tissue integrity. Many other cells can set in motion an inflammatory gene expression program; however, obvious quantitative and qualitative differences exist when different cell types are exposed to the same inflammatory agent, suggesting that the cellular context is a main determinant of the transcriptional output. Macrophages themselves show a remarkable plasticity in their gene expression programs and can dramatically change their functionality when exposed to different microenvironments. A major interest of the lab is to clarify the molecular mechanisms controlling macrophage gene expression and in particular the inflammatory gene expression program. In the last years, we have started using extensively genomic approaches and in particular chromatin immunoprecipitation coupled to high-throughput sequencing to address some basic aspects of the inflammatory gene expression program, in particular the identification of genomic regulatory regions that control genes essential for inflammation.

The second main research area relates to the mechanisms that link chronic inflammation to cancer initiation and progression. Chronic inflammation is a common cause of epithelial cancers in various organs. However, a detailed molecular understanding of how inflammation leads to the changes in sequence, structure, organization and ultimately functionality of the genome that underlie all cancers, is still lacking. Genomic alterations during cancer development are accompanied by epigenetic changes, namely alterations in the post-translational modifications of DNA and associated proteins (mainly histones). These modifications (marks) impact on accessibility, usage and stability of the underlying genomic information, and in some cases can be autonomously transmitted across mitosis. Most importantly, chromatin modifications can be modulated by environmental cues: for instance levels of DNA methylation in experimental models and, in specific contexts, also in humans, are affected to the dietary income of folic acid. Therefore, an attractive possibility is that chronic inflammation may promote cancer by inducing a progressive deterioration of chromatin marks. This is now being tested in the lab using mouse models of multi-stage carcinogenesis.

1)G. Natoli, S. Ghisletti, I. Barozzi
The genomic landscapes of inflammation
Genes & Development 25, 101-106 (2011)
2)Natoli G.
Maintaining Cell Identity through Global Control of Genomic Organization.
Immunity Jul 23;33(1):12-24 (2010)
3)De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK, Muller H, Ragoussis J, Wei CL, Natoli G.
A large fraction of extragenic RNA pol II transcription sites overlap enhancers.
PLoS Biol. May 11;8(5):e1000384 (2010)
4)S. Ghisletti, I. Barozzi, F. Mietton, S. Polletti, F. De Santa, E. Venturini, L. Gregory, L. Lonie, A. Chew, C.L. Wei, J. Ragoussis, G. Natoli
Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages.
Immunity Mar 26;32(3):317-28. Epub 2010 Mar 4 (2010)
5)L. Giorgetti, T. Siggers, G. Tiana, G. Caprara, S. Notarbartolo, T. Corona, M. Pasparakis, P. Milani, M. L. Bulyk, G. Natoli
Non-cooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs.
Molecular Cell 37, 418-428 (2010).
6)G. Natoli
Control of NF-kappaB-dependent Transcriptional Responses by Chromatin Organization.
Cold Spring Harbor Perspect Biol. Oct;1(4):a000224 (2009).
7)G. Natoli
Chromatin-mediated control of gene expression in innate immunity and inflammation.
Handbook of Cell Signalling 2nd edition (Bradshaw and Dennis eds., Academic Press) pp. 2461-2466 (2009).
8)F. De Santa, V. Narang, Z. H. Yap, B. Khoramian Tusi, T.Burgold, L. Austenaa, G. Bucci, M. Caganova, S. Notarbartolo, S. Casola, G. Testa, WK. Sung, CL. Wei, and G. Natoli
Jmjd3 contributes to the control of gene expression in LPS-activated macrophages.
EMBO J. 28, 3341-52 (2009).
10)G. Natoli
When sirtuins and NF-kB collide.
Cell 136, 19-21 (2009).
11)van Essen D, B. Engist, G. Natoli, Saccani S
Two modes of transcriptional activation at native promoters by NF-kappaB p65.
PLoS Biol. 7(3):e73 (2009).
12)G. Natoli and S. Chiocca
Nuclear ubiquitin ligases, NF-kB degradation and the control of inflammation.
Science Signaling, January 8, pe1 (2008).
13)G. Natoli and L. Austenaa
A birthday gift for TRADD.
Nature Immunol. 9, 1015-106 (2008).
14)De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G
The histone H3 Lysine 27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.
Cell 130, 1083-1094 (2007).

No projects are available to students for the current accademic year.