From bacteria to you: The biological reactions that sustain our rhythms

Summary: Researchers uncover an intimate connection between methylation and the body’s circadian rhythms.

Source: Kyoto University

Every second of every day, countless biochemical reactions take place in our bodies’ cells. The organization of this complex system is the result of billions of years of evolution, fine-tuning our functions since the first primordial organisms.

One such vital reaction is ‘methylation’, where a methyl group — a carbon atom linked to three hydrogen atoms — attaches itself to a target molecule. Methylation is involved in the regulation of everything from DNA to proteins, and it is so vital that it can be found in all living organisms.

In a recent paper published in Communications Biology, a team of researchers lead by Jean-Michel Fustin and Hitoshi Okamura from Kyoto University’s Graduate School of Pharmaceutical Sciences has uncovered an intimate connection between methylation and the body’s circadian rhythms: a link that exists even in organisms that don’t traditionally ‘sleep’, such as bacteria.

“Disfunction in methylation can cause any number of pathologies, from atherosclerosis to cancer,” explains Fustin. “Previously we discovered that inhibiting methylation in mice and human cells disrupted their body clocks.”

Methylation and the circadian rhythm, he adds, are ancient mechanisms retained in many organisms from bacteria to humans. “So, we hypothesized that the link between the two was also ancient.”

The team began by collecting cells and tissue samples from different organisms and measuring their biological rhythms. On average, all organisms run on periods of 24 hours.

The next step was to find out what happens when methylation is disrupted, and as anticipated, significant alterations in the circadian clock were detected in all cell types, including in plants and algae. However, cyanobacteria — photosynthetic bacteria — seemed relatively resistant.

“The methylation pathway in bacteria is slightly different from other organisms. But when an alternative compound inhibiting a different part of methylation was used, the circadian clock was indeed strongly affected there as well,” Fustin continues.

This is a diagram from the study
Biological methylation and the body clock are conserved during 2.5 billion years of evolution, to the extend that reprogramming the mammalian methyl cycle using a bacteial enzyme prevents methylation deficiencies is viable. Image is credited to Kyoto University/Jean-Michel Fustin.

Applying their findings, the team then took a gene that is key in controlling bacterial methylation and introduced it into mouse and human cells. Exceptionally, the bacterial gene was able to protect the cells from the first methylation inhibition compound, with no alterations observed in circadian rhythms.

“Not only did we find the evolutionarily conserved link between two ancient biological pathways — methyl metabolism and biological clocks — but we also opened the door to a possible new treatment for methylation deficiencies,” concludes Okamura.

“All organisms are more alike than you might think, and knowledge about how we evolved will allow us to better understand ourselves and the natural world.”

Jean-Michel Fustin is currently affiliated with the University of Manchester.

About this neuroscience research article

Kyoto University
Media Contacts:
Raymond Kunikane Terhune – Kyoto University
Image Source:
The image is credited to Kyoto University/Jean-Michel Fustin.

Original Research: Open access
“Methylation deficiency disrupts biological rhythms from bacteria to humans” by Jean-Michel Fustin, Shiqi Ye, Christin Rakers, Kensuke Kaneko, Kazuki Fukumoto, Mayu Yamano, Marijke Versteven, Ellen Grünewald, Samantha J. Cargill, T. Katherine Tamai, Yao Xu, Maria Luísa Jabbur, Rika Kojima, Melisa L. Lamberti, Kumiko Yoshioka-Kobayashi, David Whitmore, Stephanie Tammam, P. Lynne Howell, Ryoichiro Kageyama, Takuya Matsuo, Ralf Stanewsky, Diego A. Golombek, Carl Hirschie Johnson, Hideaki Kakeya, Gerben van Ooijen & Hitoshi Okamura.
Communications Biology doi:10.1038/s42003-020-0942-0


Methylation deficiency disrupts biological rhythms from bacteria to humans

The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.

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