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 these rhythms, as seen with jet lag and daylight saving time, can throw our daily functioning out of sync. Now, scientists at the University of California San Diego are getting closer to understanding how these clocks operate at their core.
Published in the journal Nature Structural and Molecular Biology, researchers from UC San Diego’s Department of Molecular Biology and Center for Circadian Biology, alongside colleagues from Newcastle University in the United Kingdom, have uncovered how circadian clocks within microscopic bacteria precisely control gene activity during the 24-hour cycle. This breakthrough was achieved in cyanobacteria, tiny aquatic organisms also known as blue-green algae.
Decoding the Bacterial Clock
The researchers discovered 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,” said Biological Sciences Distinguished Professor Susan Golden, the senior author of the study. “In that cell, that means some cellular processes are peaking at dusk and others at dawn.”
In recent years, circadian clocks have become a focal point of interest due to their central role in health and medicine. Medications and vaccinations are more effective when administered at specific times of the day to align with our circadian rhythms. UC San Diego recently appointed Amir Zarrinpar as the inaugural holder of the Stuart and Barbara L. Brody Endowed Chair in Circadian Biology and Medicine, a position aimed at accelerating research at the intersection of circadian biology and patient care.
Building a Synthetic Clock
In their 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 Mingxu Fang, the study’s first author and a former UC San Diego postdoctoral scholar now 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.”
Coauthor Kevin Corbett, a professor in the departments of Molecular Biology and Cellular and Molecular Medicine, highlighted the significance of this discovery. “It’s a completely independently evolved system,” said Corbett, an expert in structural and molecular mechanisms. His team employed cryo-electron microscopy, a cutting-edge method for understanding foundational life properties, to study the cyanobacterial clock at UC San Diego’s new Goeddel Family Technology Sandbox.
Implications for Biotechnology
With the core clock operating mechanisms in hand, the researchers built a clock that times transcription using purified components. They developed a synthetic gene expression system that could potentially be applied to other bacteria, such as Escherichia coli (E. coli), a staple in biotechnology. This system demonstrated the ability to 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. The potential applications of this research extend beyond microbial biotechnology, offering insights into human health and the management of biological rhythms.
Yulia Yuzenkova, a Senior Lecturer at Newcastle University, praised the study’s findings. “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,” she said. “This research advances our understanding of biological rhythms and supports applications ranging from microbial biotechnology to human gut health.”
As scientists continue to explore the intricacies of circadian clocks, the implications for medicine, biotechnology, and overall human health are profound. The work at UC San Diego represents a significant step forward in unraveling the mysteries of these biological timekeepers, offering hope for new innovations and treatments aligned with our natural rhythms.
