| Sažetak: | <p>Metabolism and epigenetics are tightly connected within the cell, as many chromatin-modifying enzymes use metabolites as co-factors or substrates, and the energetic state of the cell can drive the activation of several transcriptional programmes. This thesis examines the nexus between chromatin and metabolism, both at the systemic and cellular level, in two different projects. First, the impact on a panel of weight-loss drugs on the gut microbiome of obese rats is investigated through shotgun metagenomic sequencing. Results highlight a concomitant change in weight and gut microbiome composition following treatment with Sibutramine, which acts through inhibition of appetite. </p>
<p>A second project focuses on alterations induced by a gain-of-function mutation in the metabolic enzyme Isocitrate Dehydrogenase I (IDH1), which spurs production of the oncometabolite 2-hydroxyglutarate (2HG), in the context of glioma. Using an isogenic human glioma cell line (U87), either wild-type or bearing the R132H IDH1 mutation, an IDH1 inhibitor (GSK864) and a combination of multi-omics techniques, we characterize the metabolic and epigenetic alterations induced. Results suggest an uncoupling between metabolism, transcriptome and the epigenome, as treatment with an IDH1 inhibitor, while successfully rescuing the metabolic defect and promoting, upon a longer treatment, changes in gene expression, did not correct the epigenetic alterations. </p>
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