News Release

Yamanouchi Pharmaceutical Co., Ltd.

Yamanouchi Identifies Clock-Controlled Elements that Generate Gene Expression during Circadian Night Using "Systems Biology", A New Genomic Approach - Research Results Published in theNATURE

August 1 ,2002

Tokyo, Japan -August 1, 2002- The Molecular Medicine Laboratories (director: Kiyoshi Furuichi) of Yamanouchi Pharmaceutical Co., Ltd. (president: Toichi Takenaka) elucidated the mechanism by which circadian night is generated in the mammalian body using systems biology, a new genomic approach. They identified control elements of gene expression during circadian night. This is a new achievement in the company's genomic drug discovery research. The findings was reported in the August 1 issue of the Nature, the world-famous scientific journal published in the UK.

In the study, a group of researchers from the company analyzed the mechanism of the circadian clock that controls biological rhythms using a method based on the new science called "systems biology." At first, the group comprehensively extracted, using GeneChips, genes that periodically expressed with circadian period in organs that are controlled by the circadian clock. They then screened control elements of gene expression during circadian night by bioinformatics and demonstrated, using living cells, that these elements are actually critical for the night-specific gene expression. This work has been conducted under the leadership of Hiroki R. Ueda of Yamanouchi Pharmaceutical Co., Ltd. as part of the Genome Informatics Technology Development and Research Project commissioned by the New Energy and Industrial Technology Development Organization (NEDO). The researchers obtained suggestions and advice from a number of research organizations, including Kinki University School of Medicine and the Institute of Medical Science of the University of Tokyo.

Suprachiasmatic nuclei located in the brain ticks away like the oscillator of a clock and controls 24-hour rhythms for various physiological functions, such as sleep, awakening, changes in blood pressure and body 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 reported by the Yamanouchi researchers open a way to the prevention and treatment of various diseases that are caused as a result of disorders of these rhythms.

The research results open a new avenue to the determination of complex and minute genetic networks using a huge amount of information obtained by genomic, molecular and cell biological techniques and to efficient acquisition of genes that hold the key in the control of various biological events and diseases. For this purpose, a number of new technologies are combined, including the latest informatics technologies such as the simulation technology necessary to reproduce complex biological events on a computer and the biostatistics technology necessary to extract valuable information from a huge amount of information, as well as technologies to temporally and spatially analyze protein dynamics in living cells and to measure genome-wide gene expression. The new method is expected to serve as basic technology in applying systems biology to drug discovery research. This method is also useful in reducing the number of processes in time- and money-consuming biological experiments, such as the preparation of transgenic mice, by repeating virtual experiments on a computer (virtual laboratories), thereby increasing the research efficiency, speed, and probability of success.

Yamanouchi places top priority on genome based technologies in drug discovery and is strengthening its in-house research systems and aggressively promoting strategic alliances with bioventure companies in Japan and abroad. A number of new drug discovery targets discovered through its genomic drug discovery research have already entered the preclinical research stage. The company is committed to further accelerating the acquisition of new genes and their use in drug discovery research in order to develop breakthrough drugs with unique mechanisms of action.

About systems biology

Systems biology is a new science that aims at "understanding of organisms as systems." A new approach has been initiated in order to understand the mechanisms for control of gene expression, metabolic pathways, and signal transduction networks as systems as a result of the progression of the development of systematic analytical methods in genome and proteome. Researchers at Yamanouchi extracted a group of genes (components) related to biological events (biological rhythms), determined the network of these genes based on genomic sequences and other information, and analyzed the system construction for these biological events (biological rhythms) using GeneChips, which make it possible to comprehensively analyze gene expression, and succeeded in elucidating part of these mechanisms.


Hiroki R. Ueda, Wenbin Chen, Akihito Adachi, Hisanori Wakamatsu, Satoko Hayashi, Tomohiro Takasugi, Mamoru Nagano, Ken-ichi Nakahama, Yutaka Suzuki, Sumio Sugano, Masamitsu Iino, Yasufumi Shigeyoshi, and Seiichi Hashimoto: A transcription factor response element for gene expression during circadian night. Nature Vol. 418, pp 534-539


Mammalian circadian clocks consist of complex integrated feedback loops that cannot be elucidated without comprehensive measurement of system dynamics and determination of network structures. To dissect such a complicated system, we took a systems-biological approach based on genomic, molecular and cell biological techniques. We profiled suprachiasmatic nuclei and liver genome-wide expression patterns under light/dark cycles and constant darkness. We determined transcription start sites of human orthologues for newly identified cycling genes and then performed bioinformatical searches for relationships between time-of-day specific expression and transcription factor response elements around transcription start sites. Here we demonstrate the role of the Rev-ErbA/ROR response element in gene expression during circadian night, which is in phase with Bmall and in antiphase to Per2 oscillations. This role was verified using an in vitro validation system, in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence. The induction of circadian rhythms was detected and biologically verified as a result of the transfection of response elements.