Scientists discover new gear in human biological clock

January 14, 2021

"Junk DNA" backs the human biological clock. (Unsplash/Jon Tyson)

The biological clock in humans is bolstered by more than 100 strands of microRNAs, parts of so-called “junk DNA” that stop protein production, according to a paper published in Proceedings of the National Academy of Sciences. The study introduces a new dimension to understanding the 24-hour cycles in cells throughout the body.

The newly found role of microRNAs, researched by a team of California scientists, may open new opportunities to treat an array of conditions affected by circadian rhythms.

MicroRNAs, sometimes abbreviated as miRNAs, are short single strands of nucleotides in cell nuclei that selectively block proteins from being created. Discovered less than 30 years ago amid “junk DNA,” they bind to and cripple messenger RNAs, which transport instructions to build proteins. 

Previous research had identified a few individual microRNAs that play roles in circadian rhythms, which align animals and plants with the length of a day and influence behaviors such as sleeping, releasing hormones and flowering. But they did not create a comprehensive picture of how many more kinds of microRNAs could be involved, said Steve Kay, the study’s senior author and a professor of neurology, biomedical engineering and quantitative computational biology at the University of Southern California.

Kay and his research team tested nearly 1,000 microRNAs in humans by adding synthetic imitations to cell cultures, which were programmed to visualize their circadian clocks by glowing more or less throughout the day. They found that 120 of the tested microRNAs affected circadian rhythms, changing either the length or strength of the cells’ 24-hour periods. 

The results revealed a greater influence from the RNA strands than the researchers expected and left them “blown away,” according to Kay.

“It was really surprising to us that there were that many hits from miRNAs,” said Kay, whose lab has been investigating the molecular and genetic basis of circadian rhythms for the past 25 years.

The researchers validated their results for three of the microRNAs, which were known to create a cluster whose influence on circadian rhythms was previously suggested but without direct evidence. By individually inactivating them in the human cells, they were able to create changes in the biological clock that were opposite of what happened when more of each microRNA was added in the previous step.

The cluster’s influence was also confirmed in mice studies, in which production of the three microRNA was disabled in specimens. Biological clocks in three of the mice’s organs were disrupted in different ways, moving them more out of sync and altering some of their period lengths and amplitudes. The mouse experiment demonstrated that these microRNAs are crucial to the function and stability of circadian rhythms, Kay said.

“We were able to validate that screen and show that at least in some cases, these hits are very, very real, and these things are really important for clock function in vivo,” he said.

The research team worked alongside The Genomics Institute of the Novartis Research Foundation in San Diego, which provided the library of microRNAs as well as screening equipment for the experiment. The foundation is owned and funded by Swiss pharmaceutical company Novartis.

The study’s authors said their paper is a resource for scientists interested in further exploring how each of the 120 identified microRNAs interact with circadian rhythms and the associated genes.

And by revealing new functions of many microRNAs, Kay hopes his lab can also augment the search for treatments of circadian rhythm-related diseases. Issues in regulating the biological clock are known to cause sleep or metabolic disorders and arise in cancers and Alzheimer’s disease. The clock’s hormone regulation is also why heart and asthma attacks are respectively more common in the day and night.

“We think that the science is well ahead of the medicine in circadian biology, but that the medicine is coming,” Kay said.

The article, “A genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms” was published Jan. 5 in Proceedings of the National Academy of Sciences. The authors of the study were Lili Zhou, Caitlyn Miller and Steve Kay, University of Southern California; Loren Miraglia and Angelica Romero, Genomics Institute of the Novartis Research Foundation; and Ludovic Mure and Satchidananda Panda, Salk Institute for Biological Studies. The lead author was Lili Zhou.

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