The central role of metabolic rewiring during cancer progression is undeniable, but its direct impact on chromatin functions has been poorly investigated.
We recently described that enzymes of central metabolism can localize on chromatin in cancer cells. However, their chromatin-associated roles remain mostly elusive. Therefore, the scope of our research is to dissect the role of enzymatic activities on chromatin, with a particular focus on cancer. To do so, we apply chemical biology and functional genomics approaches to unbiased chromatin reporters (REDS) for selected metabolic enzymes. We aim to identify the molecular networks defining the direct interplay between chromatin and cancer metabolism. Our research focuses on a brand-new area of cancer biology and has the potential to uncover novel chromatin-associated metabolic vulnerabilities.
The breakthrough aspect of our investigation has been recognized by the European Research Council which, in 2019, awarded us with one of the prestigious ERC starting grant.
Epigenetic regulation and metabolism are of great interest in cancer research. However, physical and functional connections between these two areas remain largely unexplored. While it is commonly believed that metabolites can randomly distribute inside the cell, recent evidence rather favors the hypothesis that production of certain metabolites in specific subcellular compartments orchestrates different cellular processes.
EPICAMENTE aims at exploring whether the localization of enzymatic activities on chromatin can integrate cancer metabolism with chromatin remodeling to control epigenetic regulation and tumor progression.
First, I aim at providing a dataset of chromatin-bound metabolic enzymes in a comprehensive panel of cancer cell lines. By combining a chromatin fluorescent reporter cell line strategy with epigenomic approaches, I will define the epigenetic and transcriptional scenarios orchestrated by chromatin-bound metabolic enzymes, and investigate their relevance in cancer cell proliferation.
Performing genetic screenings with the chromatin fluorescent reporter cell lines will allow the identification of genetic interactors mediating the epigenetic role of chromatin-bound metabolic enzymes. In parallel, I aim to screen for small molecules able to counteract the epigenetic states mediated by those metabolic enzymes.
Finally, I will validate my results in in vivo cancer models, thus adding an important translational aspect to the project, and opening up new opportunities for cancer therapy.
In most cases, the belief is that intracellular materials reside inside steady-state membrane-based compartments, which limit the interactions between different molecular pathways. By describing the role of chromatin-bound metabolic enzymes and discovering direct connections between cancer metabolism and epigenetic regulation, I will scrutinize this belief.