NSF-ANR: Precision of collective, distributed, dynamic gene regulation

All multicellular organisms, including humans, develop from a single cell by engaging a network of genes that activate and suppress each other in a concerted program, providing different cells with distinct, precise molecular identities. The rules of this program are only now beginning to be understood. Specifically, characterizing biophysical mechanisms that biology employs to make development robust to the inevitable randomness in molecular interactions remains a frontier question in modern developmental biology. In this project, a team of U.S. and French researchers will explore, using theoretical physics methods and computer simulations, effects of many so called “enhancers” – regions on the DNA that some genes can use to regulate others – on the precision of organism development. The team will use the fruit fly as a model organism. Understanding these effects will extend our basic scientific knowledge, and it may in the future impact human health since many diseases trace their roots to abnormalities in developmental genetic networks. The broader impacts will include training of the next generation of the workforce at the interface of physics and biology – in the participating research groups and through an international summer school organized by these groups. The focus is on building theoretical and computational models to understand the physical limits imposed by molecular architectures of gene regulatory systems on the precision and speed of regulation. The project will develop a predictive analytical and computational theory of the role of dynamical, spatially extended interactions among multiple enhancers, multiple transcription factors, and multiple promoters on precise gene regulation in eukaryotic development. Early fruit fly development will be used as an example, motivated by large amounts of existing data and the theoretical teams’ existing relationship with experimentalists. The theory will address the role of multiple proximal and distal enhancers, characterize the effects of crosstalk among various enhancers, promoters, and transcription factors on precision of gene regulation, and elucidate the constraints that the dynamical nature of the development process imposes on molecular implementations of transcriptional hubs. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France. 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.