Grant: Project Grant

Gene expression regulation is the process that allows different cells in various tissues to adopt diverse characteristics (phenotypes). The first step in gene expression is called "transcription" and consists in making a copy of the gene (a pre-messenger RNA) that will be processed into a mature RNA and ultimately translated into a protein. Human cells contain several thousands of genes that need to be differentially expressed (hence differentially transcribed) in different cells and in response to different extracellular cues (hormones for example). To achieve such a complex task, cells rely on thousands of proteins called transcription factors and co-factors. Among those proteins, 30 assemble into a large complex called Mediator. The Mediator complex plays a central role as it relays information from transcription factors to the enzyme that synthesizes the RNA molecule. Mediator is essential for life, conserved throughout evolution, and often mutated or expressed at the wrong levels in diseases such as many cancers and developmental disorders. Taking advantage of the fact that Mediator is highly conserved, our lab uses budding yeast as a model organism to dissect the mechanisms used by Mediator to regulate transcription. Using this system, we have characterized in great detail how Mediator interacts with DNA during gene transcription. We found that some Mediator subunits (proteins) are dynamically associated with Mediator during the transcription activation process. In this application, we will further dissect how this dynamic interaction is regulated and how it impacts gene expression. Our preliminary work points toward regions in Mediator that are disordered, that is that these protein regions do not fold into a defined 3D structure. We propose that these proteins use the flexibility inherent to their disordered nature to fulfill their role in regulating transcription.