Cooperativity and the Design of Gene Regulatory Circuits

The establishment and heritable propagation of gene expression states are defining features of multicellular development and are central to adaptation to new environments. Studies across eukaryotes have uncovered key molecular regulators and mechanisms involved in these processes, and produced a picture of transcription and epigenetic regulatory “circuits” with remarkable properties. In this talk, I will describe how we are using synthetic rational design approaches to illuminate design principles of these systems. Using this approach, we design and construct regulatory circuits in eukaryotic cells from the bottom-up. This allows us test different circuit designs, with precisely tailored biochemical parameters, to identify which circuits are sufficient to program regulatory function. We have been particularly focused on applying this approach to recapitulate salient features of natural chromatin-based epigenetic systems and accordingly to decipher basic requirements of epigenetic memory. We also hope that this approach will help to establish a powerful foundation for the purposeful manipulation of epigenetic regulatory systems to combat disease and program new traits in cells and organisms.