Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ChroMe (Chromatin and MetabolismChromatin-metabolism interactions as targets for healthy living)

Teaser

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...

Summary

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 are to exploit developments taking place in our molecular understanding of chromatin-metabolism interactions, setting the stage for novel therapeutic applications. In parallel, our goal is to train and develop young scientists in metabolic health and provide human capital to promote healthy aging.

We focus 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 are 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 establish an educational, networking and career development platform that allows our ESRs to exploit the translational value of chromatin factors as promising therapeutic targets and to promote and preventive medicine.

ChroMe’s scientific questions are tackled by three research work packages (WP): WP1 (Metabolite-induced transcription and healthy living) focuses on metabolite-sensing at the level of transcription factors, chromatin components and chromatin-modifying enzymes by linking mechanistic and phenotypic studies. WP2 (Epigenetic regulation of metabolic disorders) addresses how epigenetic features (DNA/histone modifications, histone variants and transcription factors) drive metabolic states at the level of organs, cell types and organelles. WP3 (Metabolomics, diagnostics & therapies) dissects how nutrition, exercise, differentiation, the microbiome and novel drugs directly impact chromatin and metabolism using phenotyping, ‘omics’ and data integration tools.

ChroMe’s training objectives are 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 addresses our objectives through the following research, training & networking instruments, including intersectorial projects and secondments, supervised by a Supervisor and Co-Supervisor, 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 (Summer School, Conference), a

Work performed

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.

Final results

Progress in WP1: We have identified a nutrient-regulated transcription factor that controls the activity of genes required for an animal’s feeding, are establishing 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 are making 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 are improving 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 are expanding 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 is facilitated by the development of novel computational approaches, which will have an impact on our entire research activity. By the end of the ChroMe funding network, we expect to have acquired significant novel insight into chromatin-metabolism interactions, established potential targets and insight toward therapeutic applications, developed novel computational approaches and – last but not least – trained a new cohort of young scientists capable of working at this exciting interface between physiology, gene regulation, systems biology and disease.

Website & more info

More info: https://www.chromenetwork.eu.