Engineering gene expression noise to modulate the collective inflammatory response

Yale University, New Haven CT

Investigators

Abstract

The significance of this project is to show how critical biological functions can be modified by synthetically engineering modest changes in the distribution of gene expression across cells, sometimes referred to as “noise”. While synthetic genetic engineering approaches are often used to change average gene expression, modulating noise is under-explored. In addition, this research seeks to improve the persistence of students in pursuing more advanced careers in science and engineering. Summer research internships in computational and molecular biology will be provided to local community college. This research will broadly impact the field of systems and synthetic biology by developing synthetic approaches to precisely modulate gene expression noise. The overall objective of this research is to systematically alter gene expression noise following activation of inflammatory signaling and demonstrate how it impacts collective cell activation of the inflammatory response in innate immune cells. The central hypothesis to be tested is that the chromatin environment at the promoter and RNA polymerase II regulation are major determinants of gene expression noise. These processes can be synthetically targeted to rationally alter cell-to-cell variability during transcription to change cell-population responses. This hypothesis is supported by preliminary data demonstrating that a promoter’s permissiveness for transcription affects transcriptional noise. To achieve the objectives of this research, CRISPR-Cas9 technology will be used to recruit epigenetic regulators to target promoters to alter gene expression noise. A mathematical model will also be developed to predict how specific molecular steps in transcription modulate noise. Finally, to explore the biological significance of modulating noise, these tools will be used to predict and test how altering transcript distributions changes the inflammatory response in a cell population. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.