RIKEN Center for Developmental Biology

2003 Annual Report

Recent large-scale efforts in genome-sequencing and expression analysis have produced an embarrassment of riches for life science researchers – biological data can now be accessed in quantities that are orders of magnitude greater than were available even a few years ago. This burgeoning set of raw data has not, however, necessarily led to equally explosive advances in the understanding of the relationships between its component parts. The need for integration has set the stage for the advent of systems biology, in which discrete biological processes and phenomena are approached as complex, interactive systems. Hiroki Ueda sees systems biology research as a multi-stage process, beginning with the identification and analysis of individual system components and their networked interactions, and leading to the ability to control existing systems and design new ones based on an understanding of structure and underlying principles.

The Ueda lab has taken the mammalian circadian clock as a relatively simple and self-contained initial model for the study of a biological system. In addition to its advantages as a basic research model, the function of the circadian clock is intimately involved in the control of metabolic and hormonal cycles, and its dysregulation is linked to the onset and symptomatology of numerous human diseases, including sleep disorders. An improved understanding at the system level promises to provide biomedical and clinical investigators with a powerful new arsenal to attack these conditions.

To address complex and dynamic biological systems such as the circadian clock, it is necessary to make comprehensive and precise measurements of the system's dynamics and to work out the organization of its underlying gene network. The Ueda lab has conducted a genome-wide screen and statistical analysis of gene expression to work out the clock-controlled genes that are rhythmically expressed in the central (suprachiasmatic nucleus; SCN) and peripheral (liver) circadian clocks. This phase of the study required the development of a genome-wide promoter database, which the Ueda lab will make available to all researchers at the CDB. Subsequent phases involved determining gene transcription start sites across the entire genome, predicting the regulatory sequences involved in time-specific transcription, and studying their actual functions in vitro using a high-throughput real-time monitoring system for luciferase-tagged transgenes. Analysis of the transcriptional regulation of gene expression in the morning, daytime, evening and night periods revealed a gene network comprising sixteen inter-regulating activators and inhibitors of time-linked gene expression.

The initial success of the systems approach to the mammalian circadian clock has been encouraging, and the Ueda lab now seeks to apply similar genome-wide, high-throughput technologies to more involved and elaborate developmental processes. Guiding that research will be Einstein's (and the system biologist's) dictum to "Make everything as simple as possible, but not simpler."