Distal regulatory elements, such as enhancers, are critical determinants of development and disease through their role in the spatio-temporal control of gene expression. The cell-type-specific activation of these regulatory regions is orchestrated by a specific subset of transcription factors, termed pioneer factors, which have the ability to bind to and (directly or indirectly) render accessible highly compacted chromatin. Each cell-type has its combination of pioneer factors which allows for the correct patterning of enhancer activity necessary to implement a specific cell identity.
Although, the field of enhancer biology is rapidly evolving, major barriers persist:
-Mapping of active regulatory elements
-Identifying the transcription factors that bind these elements
-Understanding the mechanism and kinetics with which these factors regulate enhancer activation and activity
-Defining the target genes of these regulatory elements.
Answering these questions is imperative to get a better grasp of how cellular determination is established or hijacked, in detrimental cases such as cancer.?
Here, we will tackle these issues within the context of a unique yet well-characterized dynamic model system of cell reprogramming, the Epithelial-to-Mesenchymal Transition (EMT). During this reprogramming, normal human mammary epithelial cells undergo multiple phenotypic changes and acquire a more apoptosis-resistant, migratory and invasive state. This process is crucial during embryogenesis, tissue repair and tumour metastasis. It has also been shown to be a source of cancer stem cells, suggesting that understanding mechanisms of cell reprogramming during the EMT may be crucial to efficiently treat cancer recurrence and resistance to treatment.
Using a combination of candidate-basd and unbiased approaches, with this project, our goal is to provide a dynamic blueprint of how pioneer factors and enhancers rewire the cell’s identity during the epithelial-to-mesenchymal transition.
Monsieur Andrew Oldfield (Centre national de la recherche scientifique)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CRCM Centre de Recherche en Cancérologie de Marseille_ Inserm
IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire
IGH Centre national de la recherche scientifique
Help of the ANR 451,040 euros
Beginning and duration of the scientific project: March 2023 - 42 Months