The inflammatory gene expression program in macrophages: An integrative approach for the systematic characterization of transcriptional co-regulators

Project Information

MEDICI

Grant agreement ID: 692789

DOI

10.3030/692789

Project closed

EC signature date 27 July 2016

Start date 1 November 2016

End date 31 October 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy

Periodic Reporting for period 4 - MEDICI (The inflammatory gene expression program in macrophages: An integrative approach for the systematic characterization of transcriptional co-regulators)

Reporting period: 2021-07-01 to 2022-10-31

Summary of the context and overall objectives of the project

The inflammatory response is critical for the elimination of noxious and infectious agents as well as for the restoration of the integrity of damaged tissues. As many inflammatory diseases such as Rheumatoid Arthritis and Inflammatory Bowel Diseases have a very high prevalence in the European population and because they cause a massive economic, societal and individual burden, understanding the molecular bases of normal and pathological inflammation is a critical scientific objective with significant biomedical implications.
The activation of the inflammatory response requires the deployment of a complex gene expression program that has to be carefully adapted to the type of damage and to its intensity. Thanks to the rational combination of a panel of genomic technologies, many of the regulatory mechanisms that control changes in gene expression triggered by inflammatory stimuli have been clarified in the last years. However, the macromolecular machineries working in the nucleus of mammalian cells and involved in the control of inflammatory gene expression, are largely unknown. This project aimed at contributing to fill such knowledge gap by integrating genetics with high throughput genomic sequencing approaches and advanced computational and mathematical data analyses.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The activities carried out in the course of the project resulted in several scientific outcomes. First, we have optimized and implemented advanced experimental and modelling approaches for the analysis of changes in the accessibility of the thousands of regulatory elements contained in the mammalian genome that are required for the implementation of the inflammatory gene expression program. These novel approaches allowed us to identify essential regulatory principles that explain at high resolution how the usage of the regulatory information in the genome is controlled in response to different inflammatory stimuli. Second, a medium-throughput screening for transcriptional coregulators (namely, machineries involved in the modification of chromatin and/or in the regulation of gene expression) led us to identify a panel of regulators required for the proper control of the inflammatory programs as well as to prevent the unwanted activation of potentially noxious repeat elements in response to inflammatory stimuli. Finally, we identified unexpected links between a family of enzymes controlling energy metabolism and transcriptional control that in principle may provide novel entry points for anti-inflammatory therapies.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project allowed us to identify previously unknown regulators and mechanisms involved in the control of the inflammatory response as well as, more in general, in the control of inducible gene expression in mammalian cells, in the control of extragenic transcription as well as in the regulation of repeat element activation upon macrophage activation by inflammatory stimuli

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