Formerly thought to be ‘junk DNA,’ microRNAs (miRNAs) are small chains of about two dozen non-coding nucleotides. They are emerging as important regulators of diverse physiological and pathological processes. However, our knowledge of their potential role in regulation of circadian rhythms is limited. In new research, a team of U.S. scientists successfully identified mature miRNAs as cell-autonomous circadian modulators.
Zhou et al. revealed that the miR-183/96/182 cluster has functional impacts on circadian rhythms in mammals; they can modulate circadian systems either by direct targeting of the core clock machinery or through a more indirect mechanism that ultimately feeds into the circadian clock. Image credit: Kelvin Ma / CC BY 3.0.
“We’ve seen how the function of clock genes are really important in many different diseases,” said Professor Steve Kay, a researcher in the Keck School of Medicine at the University of Southern California, Los Angeles.
“But what we were blind to was a whole different funky kind of genes network that also is important for circadian regulation and this is the whole crazy world of what we call non-coding miRNA.”
The researchers conducted the first cell-based, genome-wide screening approach to systematically identify which of 989 miRNAs might be the ones modulating circadian rhythms
“Much to our surprise, we discovered about 110 to 120 miRNAs that do this,” Professor Kay said.
The authors then verified the impact on circadian rhythms by inactivating certain miRNAs identified by the screen in their line of glowing cells.
Knocking out the miRNAs had the opposite effect on the cells’ circadian rhythm as adding them to the cells.
The scientists also focused on the physiologic and behavioral impacts of miRNAs.
They analyzed the behavior of mice with a particular cluster of miRNAs inactivated — miR-183/96/182 — and saw that inactivating the cluster interfered with their wheel-running behavior in the dark compared with control mice.
They then examined the impact of the miRNA cluster on brain, retina and lung tissue, and found that inactivating the cluster affected circadian rhythms in a different way in each tissue type — suggesting that the way the miRNAs regulate the circadian clock is tissue specific.
Understanding the impact of miRNAs on the circadian clock in individual tissue could reveal new ways of treating or preventing specific diseases.
“In the brain we’re interested in connecting the clock to diseases like Alzheimer’s, in the lung we’re interested in connecting the clock to diseases like asthma,” Professor Kay said.
“The next step I think for us to model disease states in animals and in cells and look at how these microRNAs are functioning in those disease states.”
The study was published in the Proceedings of the National Academy of Sciences.
_____
Lili Zhou et al. 2021. A genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms. PNAS 118 (1): e2020454118; doi: 10.1073/pnas.2020454118
