Our circadian clocks play a crucial role in maintaining our health and well-being, synchronizing our 24-hour biological cycles with light and dark exposure. Disruptions in these rhythms, such as those caused by jet lag or 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.
In a groundbreaking study published in the journal Nature Structural and Molecular Biology, researchers from UC San Diego’s Department of Molecular Biology and Center for Circadian Biology, together with colleagues from Newcastle University in the United Kingdom, have deciphered how the circadian clocks within microscopic bacteria precisely control gene activity during the 24-hour cycle.
Breakthrough in Cyanobacterial Clocks
The team focused their research on cyanobacteria, tiny aquatic organisms also known as blue-green algae. They discovered the connections between the 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,” explained Biological Sciences Distinguished Professor Susan Golden, the senior author of the study.
This discovery highlights the intricate dance of gene expression orchestrated by circadian rhythms, which have become a focal point of research due to their significant role in health and medicine. Medications and vaccinations are known to be more effective when administered at specific times of day, aligning with our circadian clocks.
Implications for Medicine and Biotechnology
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 designed to accelerate research at the intersection of circadian biology and patient care. This new study identified the minimal elements required 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, noted the significance of this cyanobacterial clock discovery, as it differs 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, a powerful method for understanding foundational life properties. This part of the study took place at UC San Diego’s new Goeddel Family Technology Sandbox, a center equipped with cutting-edge instruments.
Future Applications and Research Directions
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.
Yulia Yuzenkova, a Senior Lecturer at Newcastle University, remarked on the simplicity and elegance of the 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.”
The implications of this research extend beyond basic science, offering potential innovations in biotechnology and medicine. As scientists continue to unravel the mysteries of circadian clocks, the potential for new therapies and biotechnological applications grows, promising advancements in both human health and industrial processes.
