Grant: Project Grant

Regulatory elements are DNA fragments of the genome that respond to the biochemical state of cells to control expression of genes in space and time within complex organisms. The resulting specificity of gene expression control (where, when, how much) is thus encoded in the DNA sequence. Most previous work has focused on understanding differences in regulatory element function either within a fixed cellular state (in one cell type), or across highly distinct, discrete cellular states (across different cell types). However, along differentiation trajectories throughout which cells change states, cells can occupy a continuum of intermediate states. Importantly diseased cells, such as some cancer cells, often only partially complete developmental transitions and display hybrid character between the starting and end states. This provides a strong biomedical rationale to design regulatory elements that are active precisely in such intermediate states. Working in an important developmental transition in pancreatic cancer progression and leveraging genomics method development, high-content single-cell functional profiling, and predictive mathematical modeling, we will engineer regulatory element 'sensors' that are actuated only in hybrid cellular states along developmental trajectories. Accomplishing this goal requires pushing the limit of our quantitative understanding of the transcriptional cis-regulatory code.