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

Informations projet

MEDICI

N° de convention de subvention: 692789

DOI

10.3030/692789

Projet clôturé

Date de signature de la CE 27 Juillet 2016

Date de début 1 Novembre 2016

Date de fin 31 Octobre 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 500 000,00

Contribution de l’UE

€ 2 500 000,00

Coordonné par

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)

Période du rapport: 2021-07-01 au 2022-10-31

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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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