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Chromatin and Metabolism Chromatin-metabolism interactions as targets for healthy living

Periodic Reporting for period 2 - ChroMe (Chromatin and MetabolismChromatin-metabolism interactions as targets for healthy living)

Reporting period: 2018-03-01 to 2020-02-29

Obesity and diabetes impact health and have become a great burden to society. Incidences of diabetes are estimated to double by 2030, jeopardizing human health and reducing our quality of life. The EU, WHO, governments and other organizations are investing major resources to reduce the burden of this “metabolic syndrome” through better education, prevention and therapies.

Our MSCA ITN Network ChroMe (Chromatin & Metabolism) is embedded within this scientific context. Our objectives have been to exploit developments taking place in our molecular understanding of chromatin-metabolism interactions and to set the stage for novel therapeutic applications. In parallel, our goal has been to train and develop young scientists in metabolic health and provide human capital to promote healthy aging.

We have focused our attention on obesity and diabetes, which have multiple causes in our genes, nutrition and lifestyle. The overconsumption of simple sugars and alcohol, high-fat diets and/or insufficient physical activity all contribute to metabolic disorders. Metabolic enzymes, gene regulators and chromatin factors determine how nutrients affect health and disease and these proteins represent excellent drug targets. Our network’s goals were to understand how chromatin is steered by metabolism to sustain health or cause disease, and to exploit our new knowledge and expertise to develop therapies. We established an educational, networking and career development platform that allowed our ESRs to exploit the translational value of chromatin factors as promising therapeutic targets and to become highly skilled and networked practicioners of this forefront research area in biomedicine.

ChroMe’s training objectives were to: (1) Transmit broad interdisciplinary knowledge of biochemistry, epigenetics, systems biology, physiology and clinical medicine to study metabolic health and disease and to allow our ESRs to establish experimentally testable hypotheses and biomedical innovation. (2) Train advanced technical skills for hypothesis-driven research and ‘omics’ approaches, from genomes to molecules (e.g. metabolites), cells, organs and live animals, including a major, longitudinal training platform on bioinformatics, which medicine rely on in the 21st century. (3) Build clinical awareness. We will train the ability to identify unmet clinical needs and key opportunities that could improve the management of metabolic diseases. (4) Build experience to exploit opportunities by finding collaborators, approaches and resources. (5) Provide our ESRs with timely, personalized, entrepreneurial and industry-relevant transferable skills in management and communication in the field of metabolic diseases. (6) Establish a network of metabolic health peers, colleagues and employers, catalyzing ESR career progression in academia, biotech, pharma, and other health science sectors.

ChroMe addressed our objectives through advanced and collaborative research projects, research training and networking instruments, including intersectorial projects and secondments, transferable skill development, integration with local training and a dedicated mentoring team for each ESR, the exposure of our ESRs to a global community of experts and peer networking, advanced training in innovative technologies, bioinformatics and translational science, network-wide transferable skills (IPR, exploitation, career orientation, communication, project- and conflict-management, gender issues, teamwork, research integrity) and the participation of patient support groups and of each ESR in public engagement activities.
In WP1 we work on chromatin binding factors, such as transcription factors or histones, which are capable (or are predicted) to interact directly with metabolites. In addition, their binding to chromatin can be regulated by metabolites, or be induced upon an acute environmental change. This opens up the opportunity that chromatin can act as a rheostat capable of sensing metabolism.

In WP2 we work on how chromatin mechanisms determine gene activity, thus governing also the abundance of metabolic enzymes and metabolic activity and ultimately phenotypic health or disease. We are making good progress in dissecting how chromatin regulation impacts on all these levels.

In WP3 we work on chromatin-modifying enzymes whose activity depends on metabolites, thus linking gene activity to metabolism. Further, the gut microbiome dictates the nutrients we absorb, including metabolic substrates of epigenetic regulators. Since the microbiome is influenced by age and diet, it has the potential to influence metabolic disease.

Our activities have generated a total of 46 breakthrough publications and poster presentations in top journals and international conferences and workshops. Moreover, ChroMe investigators and their ESRs have organized or co-organized 19 conferences and workshops, participated in 279 such events, held 64 guest seminars and participated or organized 32 outreach activities. Notable examples include a publication by Nature Structural & Molecular Biology by ChroMe investigators Buschbeck, Ladurner, Pospisilik and Yanes (2017, vol. 24, pp. 902-910), the launch of the startup biotech company Eisbach Bio GmbH by Ladurner (2019).
Progress in WP1: We have identified a nutrient-regulated transcription factor that controls the activity of genes required for an animal’s feeding, have established pioneering links between a sugar-sensing mammalian transcription factor and a particular post-translational modification, are accumulating evidence for the important role of the energy cofactor NAD+ in the regulation and function of a chromatin component and as a critical regulator of the circadian clock.

Progress in WP2: We have made progress in understanding the role of a transcription factor in the susceptibility for common forms of type 2 diabetes and are conducting a screen for chromatin regulators that affect fatty acid metabolism and have been dissecting the contribution of particular epigenetic factors to the regulation of metabolic phenotypes in mice, as well as identifying the role of histone deacetylases in jojo-dieting.

Progress in WP3: Here we have improved our understanding of how nutrition modulates gene regulation. Specifically, we are advancing our understanding of how nutrients modulate the circadian clock, while also applying mass spectrometry approaches to measure changes in histone modifications. We are assessing the impact of how novel compounds regulating metabolism correlate with histone modifications, and have expanded on the role of the gut microbiome in determining blood metabolite levels and histone modification patterns.

Further, the integration of genome-wide results from genomics approaches together with physiological and metabolic data has been facilitated by the development of novel computational approaches, which has impacted our entire research endeavour. By the end of our project, we will have acquired significant novel insight into chromatin-metabolism interactions and toward therapeutic applications, developed novel computational approaches and – last but not least – successfully trained an interactive, highly networked new cohort of ambitious young scientists with demonstrated skills and expertise of working at this medically-important interface between physiology, nutrition, gene regulation, systems biology and human disease.