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Control of metabolic and inflammatory pathways by nuclear receptors

Final Report Summary - NR-NET (Control of metabolic and inflammatory pathways by nuclear receptors)

NR-NET is a multidisciplinary consortium, whose activities were directed towards the understanding of the role of Nuclear Receptors (NRs) and coregulators in metaflammatory disease. Metaflammation - metabolic disorders linked to chronic inflammation – is a concept explaining the pathogenesis of a wide-spectrum of diseases. Several nuclear receptors were found to directly sense metabolic alterations and function as important endogenous modulators of metaflammatory pathways further expanding the repertoire of diseases that can be intervened by NR-modulating drugs.
NR-NET has delivered important new knowledge on the basic biological processes involved in the mechanism of epigenetic control of gene expression by nuclear receptors and on different structural and functional aspects of nuclear receptor action, as well as provided a better understanding of the pathogenesis of metabolic disorders and inflammation.
Below are highlights of the major scientific achievements of the NR-NET consortium: a) Several important mouse models for studying NR- or coregulator-mediated metaflammation pathways have been generated. These include knock-out and transgenic mice for histone methylases, acetylases, deacetylases, GPS, PPARg, Pgc1 a and Pgc1b and other cofactors; b) identification of novel pathways, co-regulated by distinct nuclear receptors; c) We generated global gene expression profiles in liver, adipose tissue, intestinal epithelium and macrophages under different physiological and pathological conditions; d) We generated genome-wide occupancy maps of NRs in different cell types and physiological conditions; e) Combined analyses of phenotypes and “omics” data established the roles of most of the studied factors in different biological pathways; f) The role of Pgc1 isoforms in Inflammatory Bowel Disease and hepatocellular carcinoma has been established; g) A new function of SAGA complex has been identified. It involves deposition of histone modifications in gene bodies; h) A beneficial effect of HDAC inhibition in obesity-related insulin resistance has been discovered; i) Two distinct populations of GTF complexes with different functional roles has been identified; j) A regulatory role of GPS2-containing NR coregulator complexes has been identified in inflammatory processes and obesity; k) hierarchical chromatin and transcriptional reprogramming mechanisms have been identified in macrophage populations; l) the mechanism of circadian oscillations of NR-regulated genes has been described; m) Detailed structural and functional features of HDAC-containing protein complexes have been obtained. The scientific achievements have been published in 97 peer journals and 5 book chapters and presented in numerous conferences (21), workshops and seminars.
Apart of the above scientific achievements, NR-NET has also completed a successful training program. As originally planned, the research was conducted under the framework of a structured training program, which included a large number of Individual and Network-wide training activities. The main objective of the training program was to provide opportunities for acquiring skills and expertise in: a) Structural and functional aspects of NR-regulated gene expression b) Genomics and proteomics approaches to analyze complex regulatory networks c) Systems biology approaches and bioinformatics tools to define composite regulatory modules d) Studying metabolic and inflammatory pathways in model organisms with an ultimate goal of better understanding the pathogenesis of metabolic disorders and inflammation. In parallel to training in academic and industry-based research projects, specific emphasis was given to training in transferable skills and the stimulation of creativity and entrepreneurial mindset of young researchers.
As part of the network-wide activities, NR-NET has organized 5 Workshops, 2 Conferences and participated in 2 Advanced Lecture Courses. A total of 20 young researchers (17 ESRs and 3 ERs) have benefited from the research and training opportunities offered by NR-NET. One of the main priorities of the program was to provide high quality training in the nuclear receptor field and beyond it, with focus on enhancing the career prospects and competitiveness of the fellows. To this end, each fellow from the beginning of their employment pursued a detailed career development plan (CDP), which was continuously adjusted to new scientific developments during the course of the projects.
Overall, the consortium has completed all initially proposed deliverables and as the record shows, it had a performance in both scientific output and quality training, beyond the initial expectations.
The Network'e web site can be found at the following address: