IA. Clock Genes, Clock Cells and Clock Circuits
IB. Clock Genes, Clock Cells and Clock Circuits Continued
II. Genetics of Mammalian Clocks
III. Molecular Basis of a Clock
Part IA: Clock Genes, Clock Cells and Clock Circuits
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Circadian rhythms are an adaptation to the 24 hr day that we experience. Takahashi begins his talk with an historic overview of how the genes controlling circadian clocks were first identified in Drosophila and the cloning tour de force that was required to identify clock genes in mice. He also describes the experiments that resulted in the realization that all cells in the body have a circadian clock, not just cells in the brain.
In part 1B, Takahashi explains that the suprachiasmatic nucleus (SCN) in the brain generates a circadian rhythm of fluctuating body temperature that, in turn, signals to peripheral tissues. Heat shock factor 1 is one of the signaling molecules responsible for communicating the temperature information and resetting peripheral clocks.
In Part 2, Takahashi describes how crossing many mice of different genetic backgrounds allowed his lab to identify several genes that impact the output of the clock gene system through different mechanisms.
Takahashi begins the last part of his presentation with the crystal structures of BMAL1 and CLOCK, the two central activators of clock gene transcription. He goes on to describe how his lab showed that CLOCK:BMAL1 controls the DNA binding activity of transcriptional regulators of not only cycling genes, but also of basic cell functions such as RNA polymerase II occupancy and histone modifications.
Joseph Takahashi received his BA in biology from Swarthmore College, his PhD in neuroscience from the University of Oregon, and he was a post-doctoral fellow with Martin Zatz at the National Institutes of Mental Health. He then spent 26 years at Northwestern University where he was a faculty member in the Department of Neurobiology and Physiology and in 1997 he became an Investigator of the Howard Hughes Medical Institute. In 2009, Takahashi joined the University of Texas, Southwestern Medical Center as the Loyd B. Sands Distinguished Chair in Neuroscience.
Using forward genetic screens in mice, Takahashi identified the first mammalian circadian gene “Clock” in 1997. Since then, his lab has gone on to identify and clone numerous circadian genes in both the brain and tissues throughout the body. Takahashi has received numerous awards and honors for his ground-breaking research including election to the National Academy of Sciences.
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Lowrey, P.L. and J.S. Takahashi. 2011. Genetics of circadian rhythms in mammalian model organisms. Advances in Genetics 74: 175-230. doi: 10.1016/B978-0-12-387690-4.00006-4. PMCID: 3709251.
Mohawk J.A., C.B. Green and J.S. Takahashi. 2012. Central and peripheral circadian clocks in mammals. Annual Review of Neuroscience. 35: 445-462. PMCID: 3710582. doi: 10.1146/annurev-neuro-060909-153128
King, D.P., Y. Zhao, A.M. Sangoram, L.D. Wilsbacher, M. Tanaka, M.P. Antoch, T.D.L. Steeves, M.H. Vitaterna, J.M. Kornhauser, P.L. Lowrey, F.W. Turek and J.S. Takahashi. 1997. Positional cloning of the mouse circadian Clock gene. Cell 89:641-653. PMCID: 3815553.
Buhr, E.D., S.H. Yoo and J.S. Takahashi. 2010. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330: 379-385. doi: 10.1126/science.1195262. PMCID: 3625727.
Huang, N., Y. Chelliah, Y. Shan, C.A. Taylor, S.-H. Yoo, C. Partch, C.B. Green, H. Zhang and J.S. Takahashi. 2012. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science 337: 189-194. doi: 10.1126/science.1222804. PMCID: 3694778.
Koike, N., S.H. Yoo, H.C. Huang, V. Kumar, C. Lee, T.K. Kim and J.S. Takahashi. 2012. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338: 349-354. doi: 10.1126/science.1226339. PMCID: 3694775.
Yoo, S.-H., J.A. Mohawk, S.M. Siepka, Y. Shan, S.K. Huh, H.-K. Hong, I. Kornblum, V. Kumar, N. Koike, M. Xu, J. Nussbaum, X. Liu, Z. Chen, Z.J. Chen, C.B. Green and J.S. Takahashi. 2013. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152: 1091–1105. doi: 10.1016/j.cell.2013.01.055. PMCID: 3694781.
Shimomura, K., V. Kumar, N. Koike, T.-K. Kim, J. Chong, E.D. Buhr, A.R. Whiteley, S.S. Low, C. Omura, D. Fenner, J.R. Owens, M. Richards, S.-H. Yoo, H.-K. Hong, M.H. Vitaterna, J. Bass, M.T. Pletcher, T. Wiltshire, J. Hogenesch, P.L. Lowrey and J.S. Takahashi. 2013. Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice. eLife 2: e00426. doi: 10.7554/eLife.00426. PMCID: 3622178.