Pioneering the Activation of Distal Regulatory Elements during the EMT – PADRE

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.