This research program focuses on epigenetics and chromatin in yeast spores. Yeast sporulation is a widely established model for studying meiosis. However, post-meiotic events and the final differentiation of spores remain largely unexplored. In particular, spores display a very distinct organization of chromatin, which is highly compacted, but ready to reactivate rapidly when given nutrients. We are exploring how chromatin compaction conditions the gene expression program.

We are particularly interested in the mechanisms by which tumor cells escape the epigenetic controls that govern their somatic identity, enabling them to acquire aberrant identities. In collaboration with the EpiMed platform (IAB), we have adapted a bioinformatics pipeline, which was applied to transcriptomic data from large patient cohorts to identify “off-context” gene expression in lymphoma. This innovative approach has unraveled several aberrant gene reactivations associated with patient prognosis that are being functionally investigated with the objective of identifying novel druggable cell vulnerabilities.

Diffuse large-cell lymphoma (DLBCL) is an aggressive and frequent hematological malignancy. DLBCLs are driven by major epigenetic deregulations, as they harbor many mutations in chromatin factors. DLBCL therefore represents an attractive system to study the link between epigenetic deregulation and therapeutic resistance. We are currently investigating how these alterations shape the epigenetic landscapes and how their heterogeneity conditions the emergence of persistent cell populations using cutting edge single-cell epigenomics. In this objective, we are exploiting various lymphoma models and patient cohorts to reveal novel epigenomic mechanisms of lymphoma progression and resistance.

A first project is developing new molecules capable of acting on infections by pathogenic fungi. These infections kill around 1.6 million people every year, as many as tuberculosis or malaria. The alarming increase in drug-resistant strains, combined with the toxicity, high cost and limited repertoire of available drugs, has created an urgent need for new therapeutic agents.

We collaborated with Carlo Petosa (Structural Biology, IBS) and Charles McKenna (Medicinal Chemistry, USC, Los Angeles, USA), creating the perfect opportunity to transfer our expertise on the Bdf1 protein to biomedical applications. By screening chemical libraries, we have identified small-molecule compounds that inhibit this protein in pathogenic yeasts of the Candida genus. These results could ultimately lead to the development of new classes of antifungal drugs.

We are also interested in how epigenetic inhibitors can be used to treat high-grade B lymphomas. We are particularly interested in bromodomain inhibitors, to better characterize their molecular targets and rationalize their clinical use as single agents or in combination therapies.

Finally, we are studying also the impact of a new generation of bromodomain inhibitors on the inflammatory response. We are evaluating the anti-inflammatory effect of a new generation of BET inhibitors, derived from an innovative synthesis route based on green chemistry (collaboration Yung-Sing Wong, DPM/UGA) in cellular and preclinical models of inflammation (in ovo and in a rat model of inflammation-induced hepatocellular carcinoma, (collaboration T. Decaens / Z. Macek-Jilkova, IAB/CHUGA and Inovotion).