iGReD - Genomic Imprinting and the epigenetic control of cell fate determination

Our team explores the molecular and epigenetic bases of the widespread gene transcriptional deregulation in cancer cells. We are more specifically tackling this question in malignant glioma, a widespread type of brain tumor. Through exhaustive and integrative molecular analyses conducted on samples from the Auvergne Gliomes biobank, we found that most transcriptional alterations in tumor samples were DNA methylation–independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes (Plan cancer funding, PMID: 31533980). On this observation, we are aiming to determine the cause of this alteration in H3K27me3 dynamics.  In this frame, we have identified a new non-coding RNA at HOXA locus. We evidenced an essential role of this RNA in glioblastoma initiating/stem cells (CIGs) (CLARA Funding) et we are now investigating for its mode of action (ARC and LNNC funding). In parallel, we evaluate the connection between the genome-wide DNA hypomethylation, which characterize cancer cells, and alteration of H3K27me3 dynamics.  Our original hypothesis is that hypomethylation-promoted antisens transcription from retrotransposon L1 element, can induced aberrant expression of adjacent genes that in turn will influence the H3K27me3 dynamics. This project, conducted on GICs lines (collaboration Pr. Karayan-Tapon, Poitiers), relie on innovative sequencing and bio-informatics approaches (LNCC and Fond Brou de Lauriere funding).

In addition, we determined that a combination of HOX-associated molecular signature can be used as a biomarker with a high prognostic value, better than MGMT methylation status alone. This combination of prognostic and predictive biomarkers, that remain to be validated on a larger cohort, had a favourable decision from Inserm Transfer to file a patent application.

Other partners within the GCCA​​​​

• Jean PERRIN Comprehensive Cancer Center - Pathology Department
• Jean PERRIN Comprehensive Cancer Center - Radiology Department
• Clermont-Ferrand University Hospital- Délégation à la Recherche Clinique et à l’Innovation
• Clermont-Ferrand University Hospital - Pathology Department
• CHELTER - Role of intra-Clonal HEterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
• IMoST - Tumor immune microenvironment of head and neck cancers