TRANS-TAR · Targeting transcriptional mechanisms in chronic inflammation-associated diseases

Final Activity Report Summary - TRANS-TAR (Targeting transcriptional mechanisms in chronic inflammation-associated diesases)

Inflammation is a general response of the organism to danger signals, including microbes and materials released from cells and tissues as a consequence of damage. The objective of the TRANS-TAR team was to enhance our knowledge on the basic molecular mechanisms controlling the activation of the gene expression program required to mount an inflammatory response. The scientific output during the four years of activity of the team has been remarkable and achievements exceeded the expectations and the original plan. We have first of all identified a large panel of transcriptional coregulators relevant for the induction of the inflammatory response and for some of them, like the histone demethylase Jmjd3, we have provided a detailed characterisation of their function, which included the genome-wide characterisation of its distribution using innovative approaches (De Santa et al., Cell 2007 and EMBO J, 2009). In the case of histone deacetylases, the team member involved in this activity is completing the experiments and a paper will be ready for submission in a few months. It is important to notice that both histone demethylases and deacetylases are being considered as potential targets of anti-inflammatory drugs by several major pharma companies in the world. A second relevant output has been the definition of basic principles explaining the activity of the major inflammatory transcription factor, NF-kB, applying laws of physics to biological observations and measurements (Giorgetti et al., Mol Cell 2010). Also part of this activity is still on-going in the context of a collaborative European project (Model_In), and we are now testing predictions of our models using genetics in the mouse. A third major observation has been the definition of the basic organisational principles of genomic regulatory elements of macrophages, the most important professional inflammatory cells. We have found that the whole repertoire of genomic regulatory elements in macrophages is built by the major inflammatory transcription factor, Pu.1/Sfpi). At the level of enhancers controlling inflammatory gene expression, Pu.1 binding creates small nucleosome-free and accessible areas that can be contacted by inflammatory transcription factors like NF-kB (Ghisletti et al. Immunity 2010). Moreover, we have found that RNA Polymerase II is recruited to a significant fraction of these enhancers, possibly to facilitate their opening and the maintenance of an active chromatin state (De Santa et al Plos. Biol. 2010). These observations allowed enhancing the general understanding of how a transcriptional regulatory repertoire is generated (Natoli, Immunity 2010) as well as a general definition of the basic properties of regulatory elements that control inflammatory gene expression (Natoli et al, Genes Dev. 2011). A major collateral output of the team has been the generation of several datasets (gene expression data and Chromatin Immunoprecipitation-Sequencing data) that have made publicly available to the scientific community via the NCBI website (GEO, gene expression omnibus database).

Data: CORDIS, © European Union