The internal clock of our cells is affected by mechanical forces

2023-07-05 13:30:04

Living beings have an internal biological cycle, known as circadian clock, which allows them to adapt to environmental changes resulting from the rotation of the Earth. 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 fundamental so that living beings can 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 through different time zones in a few hours.

Researchers have described the mechanism by which cells’ circadian clock is dysregulated in response to external physical forces.

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

YAP protein, key in the deregulation of the internal clock

“Recently it has been described that mechanical forces are capable of deregulating the circadian clock. What we are showing now is the molecular mechanism by which this happens,” he says. Juan F. AbenzaIBEC researcher and co-first author of the study.

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

Nearly all cells in our body have an autonomous circadian clock that controls ~40% of the genome. We show, at the single cell level, that the clock is mechanically controlled through YAP/TAZ. @IBECBarcelona pic.twitter.com/9XieM2DUIx

— Xavier Trepat (@XavierTrepat) June 28, 2023

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

Researchers have used advanced techniques of confocal microscopy, microfabrication, and custom computer analysis to study the functioning of the circadian clock in individual cells. have applied disturbances mechanical, biochemical and genetic in a controlled manner on the cells and have seen that one of the YAP “target” genes is Reverbα, a key gene in the control of the circadian clock.

The YAP protein is key in the dysregulation of the circadian clock and also controls cell proliferation

“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. Leo RossettiIBEC researcher and co-first 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 cells in the aging process.

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

Reference:

Juan F. Abenza, Leone Rossetti, Xavier Trepat, et al. “Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD”. Journal of Cell Biology (2023)

Rights: Creative Commons.