The mammalian circadian clock is thought to arise from the interactions of around 20 transcription factors with specific DNA sequences associated with morning, day, and night expression. Existing models of this genetic network can readily explain the basis for the day and night activities, but the mechanism underlying morning expression remains incompletely understood.
It is thought that delayed negative feedback exerted by the morning (E/E? box) inhibitor Cryptochrome 1 (Cry1), which is itself expressed in evening, plays an important role in keeping the biological clock on time. But just how it achieves this effect is unknown.
Maki Ukai-Tadenuma and Rikuhiro G. Yamada of the Laboratory for Systems Biology (Hiroki R. Ueda, Project Leader), along with colleagues in the Universities of Memphis (USA) and Fribourg (Switzerland), now report how delayed feedback repression is a key factor in mammalian clock function. Published in Cell, this work shows the role of Cry1 as mediator of delayed negative feedback repression and fleshes out the current understanding of the circadian circuitry.
The team began by looking into the basis for the evening expression of Cry1 using reporter genes coding for the luciferase protein to detect transcriptional activity, and found that the Cry1 promoter region induces the expression of genes carrying the daytime expression motif. A closer look at Cry1’s DNA revealed that its intronic region contains a separate sequence that induces nighttime clock genes. They next stitched together a construct including these promoter and intron regions, and ran another reporter assay to observe its behavior, and found that its expression switched on in circadian evening, suggesting that this in-between expression time is a result of the combination of day and night regulatory elements. To test this model, the team tried to rescue clock function in cells with homozygous deletions of both Cry1 and Cry2 by inducing the evening expression of exogenous Cry1. They found that while the Cry1 promoter region alone was ineffective, when the promoter and intron regions were used in conjunction, the gene’s circadian rhythmicity was restored.
Using this same set-up, Ukai-Tadenuma and Yamada next tried changing the onset time of Cry1 expression, and found that as expression neared midday, meaning that the normal phase delay was reduced, the amplitude of circadian oscillations grew smaller, in line with predictions. Similarly, prolonging the delay of exogenous Cry1 expression caused an increase in the length of the restored cycle.
The team's findings were recapitulated by a relatively simple phase vector model, which not only successfully reproduces the findings from the current study, but numerous other aspects of the circadian clock network as well.
"In 1990, Paul Hardin at Texas A&M pointed out the importance of delayed feedback repression in biological clocks, but it has taken 21 years to work out the mechanism behind it," says Ueda. "We will continue exploring whether the current minimal transcriptional network model is complete, or whether new regulatory systems remain to be discovered."[ Contact ]
Parallel computation provides deeper insight into brain function
27.03.2017 | Okinawa Institute of Science and Technology (OIST) Graduate University
Big data approach to predict protein structure
27.03.2017 | Karlsruher Institut für Technologie (KIT)
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
27.03.2017 | Life Sciences
27.03.2017 | Life Sciences
27.03.2017 | Earth Sciences