Transcription, the process where DNA is copied to RNA to eventually form proteins, is often not continuous in time, but happens in bursts of high activity, followed by periods of inactivity. These bursts result in variability in expression between cells, which can influence cell fate decisions and disease progression. In addition, tumor cell populations often show increased gene expression heterogeneity compared to normal tissues, which forms a major barrier in the efficient diagnosis and treatment. Although the source of this heterogeneity was originally thought to be genetic mutations that accumulated over time, it is becoming clear that tumor heterogeneity can also be caused by non-genetic variations, such as epigenetic or gene expression variations. It is unclear why tumors display increased variability, and how this may be beneficial for tumor progression. The overarching goal of the current study is to test the mechanistic basis and functional effect of stochastic gene expression heterogeneity.
Expression variation of a gene is affected by bursting, as changing the duration and the rate of switching between periods of activity and inactivity directly changes its cell-to-cell variation. However, even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. In this project, we aim to understand how regulatory DNA sequences and regulatory factors control bursting. In addition, we examine the effect of different bursting patterns on fitness. Overall our project will give unprecedented insight into the mechanism and function of gene expression heterogeneity, which may reveal important insight into how tumors may utilize this to select for heterogeneity.
