Détails de la réservation
- Le : 17 May 2018
- De : 11 h 00
- à : 12 h 30
- Salle : Salle de conférence
Détails de l'évènement
Camille Lobry
Genetic and Epigenetic control of normal and malignant hematopoiesis
Institut Gustave Roussy
INSERM U1170
"CRISPRi-based screening of clustered regulatory
elements reveals novel cancer dependencies."
Résumé
In the recent years, massively parallel sequencing approaches allowed the identification of hundreds of mutated
genes in cancer. Although these data gave unprecedented amount of information about mechanisms of cancer
cell maintenance and/or progression, the functional characterization of genes that are key player in regulating
cancer development remain laborious. Analysis at the single gene level often fails to identify gene or pathway
collaborations leading to transformation. Studies aimed at depicting new oncogene cooperation would involve
the generation of challenging mouse models or the deployment of tedious screening pipelines, which would be
inadequate to depict new oncogene circuitry in cancer. Genome wide mapping of epigenetic modifications on
histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory
elements, also termed as Super Enhancers. Functional annotation of these regions revealed their high
relevance during normal tissue development and cancer ontogeny. We hypothesized that these regulatory
regions could regulate simultaneously expression of genes cooperating to promote cancer development. We
thus developed a novel genome-wide CRISPRi-based screening approach using in an acute megakaryoblastic
leukemia model driven by the CBFA2T3-GLIS2 fusion and nominated super enhancer regions which are
functionally linked to leukemia progression. In particular, we pinpointed a novel super enhancer region
regulating the expression of both tyrosine kinases KIT and PDGFRA. Whereas single inhibition of these kinases
affects modestly cancer cell growth, concomitant inhibition of these two receptors synergizes to impair cancer
cell growth and survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can
identify co-regulated genes collaborating to promote cancer progression and could open new avenues for the
design of combination therapies.
Invitation : Catherine Sawaï – U1218
Responsable
- Nom : Rocher Virginie