Research

Introduction(Research Achievement)
Background: Mammalian circadian clock as a model system
LSB has taken the mammalian circadian clock as an initial model system that exhibits system-level dynamical and structural properties, in order to develop research strategies and technologies for the future study of more complex and dynamic biological systems such as mammalian development. The mammalian circadian clock consists of complexly integrated feed-back and feed-forward loops and also exhibits well-defined dynamical properties (Fig. 2-1), including 1) endogenous oscillations of an approximately 24-hour period; 2) entrainment to external environmental changes (temperature and light cycle); 3) temperature compensation over a wide range of temperature; and 4) synchronization of multiple cellular clocks despite the inevitable molecular noise. All of these factors, taken together, would be difficult to elucidate without utilizing such a system-level approach. In addition to its advantages as a basic model system for systems-biological research, the function of the circadian clock is intimately involved in the control of metabolic and hormonal cycles, and its dysregulation is associated with the onset and development of numerous human diseases, including sleep disorders, depression and dementia. An improved understanding at the system level promises to provide biomedical and clinical investigators with a powerful new arsenal for attacking these conditions.

Figure 2-1. Dynamical properties of mammalian circadian clocks. Although circadian clocks appear to be cell autonomous oscillators (1), the clock can synchronize with the environment (2). Period length is kept constant irrespective of temperature (3). In multiple-cell tissue such as SCN, the clocks synchronize with each other (4).

Research Aims of LSB during the First?five years:?
Establishment of Systems-biological Approaches to Biological Systems.
Attempt to elucidate the design principles of complex and dynamic biological systems such as the mammalian circadian clock, may require 1) identification of whole network structure through comprehensive (genome-wide) screening (System Identification); 2) prediction and validation to derive the design principle through the accurate measurement of network behaviors (System Analysis); 3) repair and control of network state toward the desired state through the precise perturbation of its components (System Control); and ultimately 4) reconstruction and design of new systems based on the design principles derived from the identified structure and observed dynamics of the original network (System Design). In the last five-year term, we have been attempting to establish such systems-biological approaches to these areas. The power of these approaches can be demonstrated in their application to specific questions in a complex and dynamic biological system such as the mammalian circadian clock.

Specific Focus: Development and Evaluation of Strategies and Technologies for Systems-biological Research.
In order to establish these systems-biological approaches, we have mainly focused on the development and evaluation of technologies and strategies for each stage of systems-biological research. For each of these processes, we have been able to report several strategies and technologies as well as their application to specific questions (Fig. 2-2). This has included the identification of clock circuits and direct clock targets driven by functional genomics (Ueda H.R. et al, 2005, Nature Genetics; Matsumoto A., Ukai-Tadenuma M., Yamada R.G. et al, 2007, Genes & Development) in System Identification; static perturbation of clock followed by quantitative measurement (Sato T.K., Yamada R.G., Ukai H. et al, 2006, Nature Genetics) in System Analysis; dynamic and quantitative perturbation of clock (Ukai H., Kobayashi T.J. et al, Nature Cell Biology, accepted) in System Control; and design of DNA elements (Kumaki Y. et al, submitted); as well as in cellulo reconstruction of network circuits (Ukai-Tadenuma M., Kasukawa T. et al, submitted) in System Design. In Section 3-I~IV, we will describe in detail strategies and/or technologies developed for each stage of our systems-biological research, in addition to their application to the specific question of mammalian circadian clocks.

Figure 2-2. Strategies and technologies for systems-biological research and their application to specific questions. Development of effective strategies and new technologies (left part of each panel) accelerated systems-biological research (right part of each panel). Genome-wide profiling (gene expression and ChIP-on-Chip) and bioinformatics is a very effective tool for comprehensive identification of complex systems (upper left panel). Development of highly quantitative dynamics monitoring assay and single-cell level monitoring assay is essential to derive the design principle of a dynamic system (upper right panel). The precisely adjustable perturbation capable of controlling the state of the system is useful for elucidation of the question related to dynamical properties of the system (lower left panel). Technology that can construct a new gene network in the cell is an ultimate technique for verifying the elucidated principles for system design (lower right panel).

Interdisciplinary interactions sometimes produce unexpected discoveries and inventions that are byproducts of the main research activities, and LSB has also experienced a number of such byproducts generated from interdisciplinary interactions between different scientific and technological skills (Fig. 2-3), including the discovery of design principles of gene expression dynamics based on interactions between genomics and physics (Ueda H.R. et al, 2004a, PNAS, on gene expression dynamics) as well as the invention of new diagnostic methods to detect the internal body-time from the interaction between genomics and statistics (Ueda H.R. et al, 2004b, PNAS, on molecular-timetable methods). The Section 3-V~VI, will also describe in detail these unexpected discovery and method.

Figure 2-3. Byproducts generated in the last five-year term of LSB. Interaction between genomics and statistics enabled the birth of new diagnostic methods to detect the internal time of the body (upper panel). This method enables the detection of body time and rhythm disorders from a single-time-point expression profile of genes. Interactions between genomics and physics led to the discovery of design principles of gene expression dynamics (lower panel). Seen in this light, interdisciplinary interactions have the potential to produce unexpected discoveries and inventions as byproducts of main research activities.

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