Title: "The role of Epromoter in the regulation of stress response genes"
Friday, November 29, 2024 at 2pm
Auditorium - Hexagone - 169 Av. de Luminy, 13009 Marseille
Composition du jury:
- Guillermo Barreto (President and reviewer)
- Aleksandra Pękowska (reviewer)
- Cyril Esnalut (Examiner)
- Sandrine Marquet (Examiner)
- Salvatore Spicuglia (Supervisor)
Abstract:
The classical definition of enhancers implies the property to activate gene expression at a distance, while promoters induce local gene expression. This basic dichotomy has been challenged by broad similarities between promoters and enhancers, in particular with the existence of Epromoters, a new type of regulatory element with both activities.
Our team previously showed that interferon-induced genes are generally found in clusters and associated with at least one induced Epromoter. Surprisingly, the key interferon response factors were selectively bound at the interferon-induced Epromoters, but not at the other promoters within the cluster. These results suggested a link between Epromoter function and stress responses. Our work hypothesis is that Epromoters regulate co-induced genes nearby by recruiting specific transcription factors in order to obtain a fast and coordinated response to stress.
Based on these findings, we developed a bioinformatic pipeline to predict the Epromoters at play in different stimulatory or stress conditions, such as heat shock, serum response, LPS stimulation, or TNF stimulation. By integrating gene expression and transcription factor binding resources, the pipeline identifies clusters of induced genes where only one of the promoters recruits the key transcription factors. I subsequently assessed the efficiency of the pipeline to predict the Epromoter-regulated cluster through reporter assay and CRISPR-Cas9 genomic manipulation in different stress responses. We propose that Epromoters function as a local hub to recruit key transcription factors required for the regulation of nearby co-induced genes in response to various inflammatory and stress conditions.
Besides, to understand the mechanistic bases of the proximal versus distal regulation, I developed and validated a dual reporter assay allowing to simultaneously measure the promoter and enhancer activity of a given Epromoter and thus, in the future, decipher the molecular bases of each activity.
