Department of Physiology and Systems Bioscience

Principles and Human Physiology
〜From the principles of circadian rhythms to human physiology and pathology〜
Living organisms acquired a circadian clock as an adaptation mechanism to the diurnal variation of day and night caused by the rotation of the Earth, which is the most fundamental environmental change. By assimilating the frequency of the Earth into the cells through the circadian clock, it became possible to maintain the orderly coordination of biochemical reactions and physiologies as homeostatic systems of our body.
What is Circadian Rhythm, for humans and all living organisms? This is our main question. Discrepancies between environmental time and the body clock is known to disrupt circadian rhythms and affect our health in various ways. The study of circadian rhythms including emergence, maintenance, and misalignment, will lead to the understanding of the mechanisms of disease development caused by certain environmental factors. We aim to elucidate the principles and solve social problems by considering the elaborate and flexible circadian rhythm, which controls environmental adaptation and temporal order to maintain our homeostasis.

01Biological clock and circadian rhythm

  The body clock is a biological device that measures the earth's rotation cycle, anticipates the arrival of morning and night, and adapts to environmental changes by actively adjusting biological functions in advance. This is the biological clock with a 24-hour cycle. In other words, the role of the biological clock, also called the circadian clock, is to tune the body's functions to the environmental changes caused by the Earth's rotation. For example, in humans, the biological clock controls not only the sleep rhythm, but also the autonomic nervous system, the endocrine system, the cardiovascular system, the digestive system, the immune system, and many other physiological functions so that they work at their optimal timing. The diurnal rhythm of these physiological functions is called the "circadian rhythm. In our laboratory, we are studying the basis of the circadian clock as an "informational mechanism of time" that assimilates the laws of motion of the earth (the laws of the universe!) into the body and adapts various biological functions to the environmental cycle. What does this internal clock mean to living organisms?
 We have recently clarified that the biological clock is not present in pluripotent stem cells such as ES cells and iPS cells, but is formed in conjunction with development and cell differentiation (PNAS, 2010). In addition, it was found that the formation of the biological clock is accompanied by synchronous adaptation to the environmental rhythms of the outside world (maternal rhythms) (PNAS, 2017). These findings suggest that the circadian clock is an interface between the external environment and the internal physiology of the body. In other words, the body clock is a physiological function that creates time order in the body in relation to the environment, and is the basic principle of the operating system of life. Interestingly, we observed the transition of two different types of rhythms during the developmental process, from segmentation clock to circadian clock (PNAS, 2022). During somitogenesis, circadian clock-mediated 24-hour temporal order is likely to be suppressed not to allow it to interfere with the segmentation clock. Our goal is to elucidate the biological control system based on the biological clock from the understanding of the principle of the circadian rhythm and the control mechanism of homeo-dynamics that penetrates the hierarchy of molecular, cellular, tissue, organ, and individual levels.

02Circadian rhythm disorder as pre-symptomatic disease

In recent years, globalization and IT have led to a shift to 24-hour urban functions. The number of shift workers, including those who work late at night, continues to increase, and it is estimated that more than 12 million people are engaged in such work. In addition, with cities filled with light even in the middle of the night, and the spread of smartphones and tablets, lifestyle changes are spreading even to children. In such a 24-hour society, it is becoming more and more difficult to maintain the normal living environment of regularity and the concept of “early to bed and early to rise”. In such a modern society, the discrepancy between the "biological clock," which originally evolved as a tuning mechanism to the earth's rotation cycle, and the time we spend in our daily lives is leading to various health problems and increased risk of diseases.
However, simply telling people to live a regular life or to go to bed early and wake up early is not a solution to the social problem. Essential workers are indispensable for a safe and comfortable society. How do environmental factors, such as deviations in lifestyle and body clocks, affect the physiological functions and cause changes in molecular mechanisms at the cellular level? Research on the mechanism of homeostasis disruption due to environmental factors is currently an uncharted field with little progress due to the barrier of individual differences. We are challenging this difficult scientific question with new approaches. Recently, we succeeded in developing a new approach named "mouse cohort model" to deduce the process of circadian disorders. Using this, we showed that the circadian misalignment resulted in deleterious consequences in mice (Sci Rep, 2020). The environmental perturbation disrupting circadian temporal order severely impairs homeostasis. We are now working to answer the question of how the environmental perturbation induces the sequence of circadian disorders.

03Human circadian physiology: From Lab to Society

 In our laboratory, we are also developing "human physiology" that aims to solve health issues in today's 24-hour society by elucidating the principles of "environmental adaptation," "pre-symptomatic state," and "individual differences."

Publication List (Selected)

1

Umemura Y, Koike N, Tsuchiya Y, Watanabe H, Kondoh G, Kageyama R, Yagita K*., Circadian key components CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids., Proc. Natl. Acad. Sci. USA, 119, e2114083119, 2022(*Corresponding author)

2

Inokawa H, Umemura Y, Shimba A, Kawakami E, Koike N, Tsuchiya Y, Ohashi M, Minami Y, Cui G, Asahi T, Ono R, Sasawaki Y, Konishi E, Yoo S-H, Chen Z, Teramukai S, Ikuta K and Yagita K*., Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice., Sci. Rep.,10, 2569, 2020 (*Corresponding author)

3

Umemura Y, Maki I, Tshuchiya Y, Koike N, Yagita K*., Human circadian molecular oscillation development using induced pluripotent stem cells, J Biol Rhythm , 34, 525-532, 2019(*Corresponding author)

4

Ikeda R, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Ono R, Inoue M, Sasawaki Y, Grieten T, Okubo N, Ikoma K, Fujiwara H, Kubo T, Yagita K*. REV-ERBa and REV-ERBb function as key factors regulating Mammalian Circadian Output., Sci. Rep., 9, 10171, 2019 (*Corresponding author)

5

Ohashi M, Umemura Y, Koike N, Tsuchiya Y, Inada Y, Watanabe H, Tanaka T, Minami Y, Ukimura O, Miki T, Tajiri T, Kondoh G, Yamada Y, Yagita K*., Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors., Genes Cells, 23, 60-69, doi: 10.1111/gtc.12552., 2018 (*Corresponding author)

6

Umemura Y, Koike N, Ohashi M, Tsuchiya Y, Meng QJ, Minami Y, Hara M, Inokawa H, Hisatomi M, Yagita K*., Involvemant of post-transcriptional regulation of Clock in the emergence of circadian clock oscillation during mouse development., Proc. Natl. Acad. Sci. USA, 114, E7479-7488, 2017 (*Corresponding author)

7

Kunimoto T, Okubo N, Minami Y, Fujiwara H, Hosokawa T, Asada M, Oda R, Kubo T, Yagita K*., A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site., Sci. Rep., 6, 22409, 2016 (*Corresponding author)

8

Tsuchiya Y, Umemura Y, Minami Y, Koike N, Hosokawa T, Hara M, Ito H, Inokawa H, Yagita K*., Effect of Multiple Clock Gene Ablations on the Circadian Period-Length and Temperature Compensation in Mammalian Cells., J. Biol. Rhythm, 31, 48-56, 2016 (*Corresponding author)

9

Umemura Y, Koike N, Matsumoto T, Yoo S-H, Zhen C, Yasuhara N, Takahashi JS, Yagita K*., Transcriptional Program of Kpna2 /Importin-α2 Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cell, Proc. Natl. Acad. Sci. USA, 111, E5039-48, 2014 (*Corresponding author)

10

Sumiyama K, Kawakami K, Yagita K. A Simple and highly efficient transgenesis method in mice with the Tol2 transposon system and cytoplasmic microinjection., Genomics, 95, 306-311, 2010.

11

Yagita K*, Horie K, Koinuma S, Nakamura W, Yamanaka I, Urasaki A, Shigeyoshi Y, Kawakami K, Shimada S, Takeda J, Uchiyama Y, Development of circadian oscillator during differentiation of mouse embryonic stem cell in vitro., Proc. Natl. Acad. Sci. USA, 107, 3846-3851, 2010. (* Corresponding author)

12

Kiyohara, Y#, Nishii K#, Ukai-Tadenuma M, Ueda HR, Uchiyama Y, Yagita K*. Detection of a circadian enhancer in the mDbp promoter using prokaryotic transposon vector based strategy., Nucl. Acids Res., 36, e23, 2008. (*Corresponding Author)

13

13. Kiyohara Y.B#, Tagao S#, Tamanini F, Morita A, Sugisawa Y, Yasuda M, Yamanaka I, Ueda H.R, van der Horst GTJ, Kondo T, and Yagita K*. The BMAL1 C terminus regulates the circadian transcription feedback loop. Proc. Natl. Acad. Sci. USA, 103, 10074-9, 2006. (*Corresponding Author)

14

Yagita K, Tamanini F, van Der Horst GT, Okamura H. Molecular mechanisms of the biological clock in cultured fibroblasts., Science., 292:278-81. 2001