CAREER: Developmental Network Architecture Underlies Patterning Precision and Robustness

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All animals begin as a single fertilized cell. During development, this cell divides and its progeny turn on distinct subsets of genes to build different types of cells like those in muscles, nerves and blood. This process is precise; tissues and organs are the correct size and shape and they occur in the correct position. This process is also robust; development unfolds accurately under a wide range of environmental and genetic assaults. Yet changes to animal physiology in disease or evolution are often due to alterations to development. This award addresses this critical paradox: how does development both buffer against change, and yet respond and adapt to change to produce new creatures? With respect to broader impacts, fewer than 10% of entering life science Ph.D. candidates will attain tenure-track academic jobs. Scientific training must therefore include skills that are useful in academia, government and the private sector. This award will support efforts to teach scientists how to communicate effectively, which is a fundamental and universally valued skill. The principal investigator will expand the scope of an innovative graduate course she directs, tailor it for undergraduates, and make modular materials available online so that other people can deploy it. This teaching effort will lead to a new generation of scientists adept at communicating across disciplines and with the public, and with skills that are highly valued in careers outside of academia. The central hypothesis is that developmental precision and robustness are encoded in the circuits of gene regulatory networks, and by extension, the regulatory DNA that wires them together. By studying how such circuits are built, and how they behave under perturbation, we can learn how they can be precise, robust and yet evolvable. Shadow enhancers, distinct pieces of regulatory DNA that drive the same target gene expression pattern, increase the precision and robustness of developmental systems but the mechanism is unknown. The DePace lab conducts their studies of gene regulatory networks in fruitfly embryos because the rules governing development are extremely similar between fruitflies and other animals, including humans, but fruitfly embryos offer substantial experimental advantages for deciphering the underlying principles. The DePace lab recently uncovered a pair of shadow enhancers in fruitfly embryos that respond to the same regulator in opposite ways. This project will interrogate the function of this novel circuit using quantitative experiments and computational models. Aim 1 will determine how the activity of the bifunctional regulator (a transcription factor) is controlled. Aim 2 will determine how the circuit affects patterning precision and robustness in the embryo. This research will: 1) probe the molecular mechanism of transcription factor bifunctionality, a general problem in interpreting the genome, 2) determine the role of a novel transcriptional circuit in embryonic patterning precision and robustness and 3) establish a powerful model for studying the mechanism and consequences of distributed regulatory DNA, which is a significant but under-studied class.