Classically, gene expression is thought to be regulated by the stable binding of one or more transcription factors to regulatory elements situated upstream of individual genes. Since the advent of genomic technologies, it has become increasingly clear that the regulation of gene expression is much more complicated than this model suggests. This proposal seeks to understand, on a global scale, a critical yet overlooked aspect of this complexity, the dynamics of transcription factor binding. Do transcription factors bind stably to DNA? Or do they disassociate at a rapid rate? How are these dynamics regulated? And how do they contribute to the regulation of gene expression? Answering these questions will contribute to the understanding of how genes are expressed in healthy as well as in diseased tissues. Specifically, I aim to measure the length of time transcription factors remain bound to specific binding sites across the entire genome. I will perform in vivo competition experiments between differentially tagged forms of the same transcription factor and determine how long it takes for one form to overtake the other, providing a measure of interaction stability. By repeating this experiment for a large number of transcription factors, I will be able to look fo emergent patterns indicative of the mechanisms regulating transcription factor dynamics. I will then explore how the dynamics of transcription factor binding relates to the organization of dynamic changes in gene expression. Ultimately, the long term goal of this work is to provide a global description of transcription factor binding dynamics and how they contribute to the regulation of gene expression.
to public health: Considerable regulation of biological systems occurs at the interface of the genome and the transcription factors that control its expression. Accordingly, a variety of disease states stem from mis-regulation of transcription factors. While many aspects of transcription factor biology have been well studied, it is not clear, in any system, how the temporal dynamics of transcription factor binding and release shape gene expression. This proposal aims to use a genetically and genomically tractable model system to probe these interactions and establish regulatory themes that can be applied to human diseases.
