News Release

Yamanouchi Pharmaceutical Co., Ltd.

Yamanouchi and RIKEN Elucidate the Heart of the Genetic Network of Biological Clock by Systems Biology -Research Results Published in the Nature Genetics

January 24, 2005

Tokyo, Japan - January 19, 2005 - The Molecular Medicine Laboratories (director: Masao Kato) of Yamanouchi Pharmaceutical Co., Ltd. (President & CEO: Toichi Takenaka) and RIKEN Kobe Institute’s Center for Developmental Biology (director: Masatoshi Takeichi), RIKEN (president: Ryoji Noyori) succeeded in elucidating the heart of the genetic network of biological clock.Their findings will be published in the online edition of the Nature Genetics on January 23.

The biological clock is a system that creates circadian (biological) rhythms of the body.Studies conducted to date have shown that 16 genes (clock and clock related genes) function as parts of the biological clock, but not how these 16 genes compose the biological clock.Researchers from Yamanouchi and RIKEN identified the heart of the genetic network of the biological clock by elucidating the entire picture of the network composed of the 16 genes.The group also clarified the principles by which the 16 genes work at specific time in the morning, daytime and night.

The biological clock controls 24-hour rhythms for various physiological functions, such as sleep, awakening, changes in blood pressure and temperature, and hormone secretion.Typical diseases and symptoms that are caused when these rhythms are disturbed include sleeplessness, depression, jetlag, refusal to attend the school, and nocturnal poriomania, a symptom associated with dementia.More recently, these rhythms have been found to affect the efficacy of drugs.The research results are expected to open a way to the discovery of preventive and therapeutic methods for various diseases caused by circadian rhythm disorders.

The research field that aims for elucidating the entire picture of genetic networks as in the work by researchers from Yamanouchi and RIKEN is called systems biology.It is a new life science field that aims for understanding dynamic and complex biological events as networks.It is expected to be a new life science that follows molecular biology.Now that the paradigm for life science is about to make a major shift following the complete elucidation of human genome sequences in 2003 and successive determination of genome sequences in various animals and plants, systems biology is attracting increasing attention as a spearhead research field in not only basic science but also applied science such as genomic drug discovery.The research results obtained by the group of researchers from Yamanouchi and RIKEN are expected to greatly contribute to the paradigm shift in life science as a model case in systems biology.

This work was mainly conducted by the group of Seiichi Hashimoto, senior research follow, Yamanouchi Pharmaceutical, as part of the Project to Develop Technology for Analyzing Dynamisms of Intracellular Networks commissioned by the New Energy and Industrial Technology Development Organization (NEDO), as well as by the laboratory for systems biology led by Hiroki R. Ueda of RIKEN’s Center for Developmental Biology. This work was also supported in part by intramural Grant-in-Aid from the CDB, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid for Strategic Programs in R & D from the Institute of Physical and Chemical Research and Grant-in-Aid for Scientific Research from NEDO. The work was supported by Kinki University, the University of Tokyo, and the National Institute of Advanced Industrial Science and Technology.

Title: System-level Identification of Transcription Circuits Underlying Mammalian Circadian Clocks
Authors: Hiroki R. Ueda, Satoko Hayashi, Wenbin Chen, Motoaki Sano, Masayuki Machida, Yasufumi Shigeyoshi, Masamitsu Iino & Seiichi Hashimoto

Mammalian circadian clocks consist of complexly integrated regulatory loops, making them difficult to elucidate without both the accurate measurement of system dynamics and the comprehensive identification of network circuits.Toward system-level understanding of this transcription circuitry, we identified clock-controlled elements on 16 clock and clock-controlled gene promoter/enhancers in comprehensive surveillances of evolutionarily-conserved cis-elements and measurements of their transcription dynamics.As a result, we demonstrated the roles of 3 elements, E-boxes/E’-boxes, D-boxes, and RREs, which are evolutionarily conserved on 9, 7 and 6 genes, respectively, and found that circadian transcriptional circuits are governed by two design principles: 1) E-box/E’-box and RRE regulations follow “repressor precedes activator” mechanism, resulting in delayed transcriptional activity; and 2) D-box regulation follows “repressor antiphasic to activator” mechanism, which generates high-amplitude transcriptional activity.We also structurally predicted by network analysis that E-box/E’-box regulation represents a topological vulnerability in mammalian circadian clocks and functionally verified this fact using newly developedin vitro phenotype assay systems.

The entire picture of transcriptional genetic networks of the mammalian biological clock