CAREER: Connectivity and Dynamics in the Transcriptional Networks

Princeton University, Princeton NJ

Investigators

Abstract

Our present understanding of intracellular regulatory networks is derived from comprehensive analysis of only a small number of well-studied genetic circuits. This deficit is more than just quantitative in nature, as we know very little about the large-scale organization of these sub-networks into the overall architecture of regulatory systems. This is akin to studying the workings of a television set by thoroughly characterizing a handful of operational amplifiers. In fact, new principles of sensory integration and processing are likely to emerge from studies that focus on the entire regulatory network of a cell. At this point, technological challenges are paramount. The biological community desperately needs methods to rapidly elucidate network connectivity (wiring) and dynamics on a global scale. This CAREER project seeks to develop experimental and computational infrastructure for mapping, monitoring, and modeling transcriptional regulatory networks in bacterial organisms. The project will: (1) develop a global, in vivo method for monitoring the occupancy of sites of DNA-protein interactions within a bacterial genome; (2) develop a high throughput, in vitro technology to identify transcription factors that bind computationally predicted and/or experimentally determined DNA regulatory sequences; (3) develop a mathematical framework for abstraction, representation, and modeling of transcriptional network dynamics. The project's long-term goal is to better understand the relationship between the structural connectivity (wiring) of transcriptional networks and their dynamics. As part of the education component of this CAREER project, a new multidisciplinary curriculum has been developed to educate graduate and advanced undergraduate students (from molecular biology, computer science, engineering, physics and chemistry) in the genomic and computational analysis of biological systems. The students will be introduced to challenging new biological questions that computational analysis, whole-genome sequencing, and other related technologies have recently made accessible. The students are expected to form inter-disciplinary teams and to carry out projects at the interface of genomics and computational biology. Much of our knowledge about the organization of cells is derived from studies of individual genes and their protein products. However, as we are getting closer to having complete parts lists for these components, we are faced with the enormous challenge of how these parts fit together to orchestrate cellular behavior at a systems level. Characterization of interactions (wiring) between molecular components is a necessary foundation for such an understanding. The class of interactions between proteins and their cognate DNA sequences (protein-DNA interactions) determine when and where genes are expressed. This CAREER project seeks to develop technologies for monitoring DNA-protein interactions on a whole-genome scale, and to relate these interactions to gene expression dynamics-laying the technological foundations for a predictive dynamical understanding of transcriptional networks.