Our circadian clocks play a crucial role in our health and well-being, keeping our 24-hour biological cycles in sync with light and dark exposure. Disruptions in the rhythms of these clocks, as with jet lag and daylight saving time, can throw our daily functioning out of sync.
University of California San Diego scientists are now getting closer to understanding how these clocks operate at their core.
In the journal Nature Structural and Molecular Biology, researchers based in UC San Diego’s Department of Molecular Biology (School of Biological Sciences) and Center for Circadian Biology, along with national and international colleagues from Newcastle University (United Kingdom), have solved how the circadian clocks within microscopic bacteria are able to precisely control when different genes are turned on and off during the 24-hour cycle.
The researchers made their discovery in cyanobacteria, tiny aquatic organisms that are also known as blue-green algae. They uncovered the links between core components of cyanobacteria’s 24-hour clock that direct the rhythmic expression of genes.
“We were able to show how a single signal from the clock can turn one set of genes on and another set off, generating opposite phases of gene expression. In that cell, that means some cellular processes are peaking at dusk and others at dawn,” said Biological Sciences Distinguished Professor Susan Golden, the senior author of the study.
Central role
In recent years, circadian clocks have become the subject of increased interest due to their central role in health and medicine. Medications and vaccinations are more effective when taken during certain hours of the day to align with our circadian clocks. UC San Diego recently named Amir Zarrinpar, professor of medicine, as the inaugural holder of the Stuart and Barbara L. Brody Endowed Chair in Circadian Biology and Medicine, a position created by the School of Medicine and School of Biological Sciences to accelerate UC San Diego’s research at the intersection of circadian biology and patient care.
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In the new study, the researchers identified the minimal elements needed to control circadian gene transcription, the first phase of gene expression, in cyanobacteria.
“We now know the components we need to rebuild this clock to generate circadian gene transcription,” said study first author Mingxu Fang, a former UC San Diego postdoctoral scholar now based at The Ohio State University. “In general, circadian systems are very complex but with this simplified cyanobacterial system we only need six proteins and we have a clock.”
Cyanobacterial clock
Coauthor Kevin Corbett, a professor in the departments of Molecular Biology and Cellular and Molecular Medicine, said the research team’s cyanobacterial clock discovery is notable because it is distinct from the clocks found in humans and other organisms known as eukaryotes.
“It’s a completely independently evolved system,” said Corbett, an expert in structural and molecular mechanisms. Corbett led the study’s use of advanced instrumentation known as cryo-electron microscopy, which in recent years has emerged as one of the world’s most powerful methods of understanding foundational life properties. That part of the study was captured at UC San Diego’s new Goeddel Family Technology Sandbox, a center that features a suite of cutting-edge instruments.
With the core clock operating mechanisms in hand, the researchers were then able to build a clock that times transcription using purified components. They developed a synthetic gene expression system that may be portable to other bacteria, such as the workhorse of biotechnology, Escherichia coli (E. coli), and showed that it can turn on a test gene rhythmically with a predictable phase of expression. “These are practical biological tools that can be expanded to control the synthesis of desirable biological products in cyanobacteria or in other kinds of microbes used in biotechnology,” said Golden.
Rhythmic pattern
Yulia Yuzenkova, Senior Lecturer, Newcastle University said: “The most remarkable aspect is that the immense complexity and variability of cellular gene activity can be orchestrated into a beautiful rhythmic pattern by a clocking mechanism so simple. This research advances our understanding of biological rhythms and supports applications ranging from microbial biotechnology to human gut health.”
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