FOXA1: function and regulation of pioneer factors

FOXA1 is the archetypal pioneer factor in hormone-dependent cancer. Pioneer factors are thought to be specialised transcription factors that determine the target genes that define cellular identity, but little is known about how they function, what their associated proteins are for functional activity and what regulates the expression and stability of these unusual proteins. In addition, little is known about specific amino acids on these pioneer factors that are required for their transcriptional activity. This proposal will provide unparalleled insight into the biology of FOXA1. The work will take unbiased approaches to identify the residues of FOXA1 that are required for its function and to discover the upstream regulatory proteins that can influence FOXA1 protein stability and activity. In addition, we will build, validate and exploit a novel approach for discovering pioneer factors and lineage-defining transcription factors from any cell type of interest. Coupled with these discovery aims, we will explore the functional connections and protein subcomplexes that exist between well-known co-factors and enzymes that have been discovered as FOXA1-associated proteins, in order to understand the dynamics of the molecular complexes, that to date, have been studied in bulk.