The internal clock of our cells is affected by mechanical forces

Living things have an internal biological cycle, known as circadian clock, which allows them to adapt to environmental changes resulting from the Earth’s rotation. Crucial physiological activities such as sleep, metabolism, hormonal variations, body temperature and blood pressure are regulated by this internal clock. In 2017, the Nobel Prize in Medicine was awarded to researchers who made important discoveries about the mechanisms that control it.

The correct functioning of the clock is essential for living beings to be able to anticipate the changes between day and night, and adapt their physiology to face them. An example of the mismatch between the circadian clock and the external environment is the disorder known as “jet lag”, which results in physiological changes in people who travel across different time zones in a few hours.

Now, a group of researchers led by Xavier Trepat, a research professor at ICREA and group leader at IBEC, has gone a step further to decipher its workings and described the mechanism by which the circadian clock of cells is disrupted in response to external physical forces. The work, the result of a collaboration between IBEC and the Pompeu Fabra University of Barcelona, ​​​​​​was published in the journal Journal of Cell Biology.

YAP protein, key in internal clock deregulation

“It was recently described that mechanical forces are capable of disrupting the circadian clock. What we are showing now is the molecular mechanism by which this happens,” he says. John F. Abenzaresearcher at IBEC and co-author of the study.

through experiments in vitro Using mouse fibroblasts, connective tissue cells responsible, among other things, for maintaining its structure, they saw that the YAP protein (Yes-Associated Protein), is the key to disrupting the circadian clock. This same protein also controls cell proliferation and is related to the development of metastases in various types of cancer.

Almost every cell in our body has an autonomous circadian clock that controls approximately 40% of the genome. We show, at the single-cell level, that the clock is mechanically controlled by YAP/TAZ. https://t.co/7R6ZlqKsOM @IBECBarcelona pic.twitter.com/9XieM2DUIx

— Xavier Trepat (@XavierTrepat) June 28, 2023

The YAP protein is the point where external mechanical signals converge and which makes cells able to perceive the rigidity of their environment. YAP is found in an inactive form in the cytoplasm of cells and, in response to mechanical stimuli, is activated and enters the nucleus, where it acts specifically on some “target” genes, initiating a response to the initial stimulus.

The researchers used advanced techniques of confocal microscopy, microfabrication and custom computer analysis to study the functioning of the circadian clock in individual cells. applied perturbations mechanical, biochemical and genetic. in a controlled manner in cells and found that one of the “target” YAP genes is Reverbα, a key gene in controlling the circadian clock.

“When a physical force affects the cell, the YAP protein moves from the cytoplasm to the nucleus and affects the Rev-erbα gene, disturbing circadian oscillations”, he explains. Leone Rossettiresearcher at IBEC and co-author of the study.

The observation that YAP alters the rhythm of cells adds a new dimension to the regulation of the circadian clock and provides elements that may help explain why it stops working correctly in cancer cells and aging cells.

Xavier Trepat, leader of the research, is also a professor at the University of Barcelona (UB) and a member of the Center for Biomedical Research Network in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN).