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Transcriptional control in inflammation and cancer

natoli

[IEO]

Gioacchino Natoli
c/o IFOM-IEO Campus
Via Adamello, 16 - 20139 Milan, Italy
Tel. 02 57489.953
gioacchino.natolimailifom-ieo-campus.it

Research project

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.

update: March 2010
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last update: February 14, 2012 . Copyright © IFOM & IEO . Campus IFOM-IEO . Via Adamello 16 . 20139 Milan Italy
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