According to a study published in Science magazine, Ueli Schibler, a professor at the University of Geneva (UNIGE), Switzerland, has identified a molecular mechanism by which body temperature rhythms influence the biological clock.

The study was conducted in collaboration with researchers at the Ecole polytechnique fédérale of Lausanne (EPFL).

During the day, numerous processes in our body fluctuate in a regular pattern. These variations can be powered by local oscillators present within our cells of by systemic signals controlled by the master pacemaker, located in the brain. In this study, the team also show how the production of a protein called DBP is modulated by daily variations in temperature. DBP is involved in detoxification and drug metabolism.

Internal clocks regulate many of our physiological functions, such as body temperature, hormone secretion and heart beat frequency. The majority of our body’s cells possess one of them, formed by a group of ‘clock genes’ displaying a cyclic activity that peaks every 24 hours. These local oscillators are synchronized by a central pacemaker, located in the brain which adapts to geophysical time by light-dark cycles.

Furthermore, the master clock controls coordination signals that are transmitted to subsidiary oscillators. Schible, a professor at the Department of Molecular Biology of the UNIGE said: “Body temperature variations constitute one of these daily resetting cues, but we did not know how it functioned.”

Due to this, the scientists created a system allowing to expose cells to simulated body temperatures cycles.

Jörg Morf, researcher at the NCCR Frontiers in Genetics, explained: “We have discovered that temperature cycles modulate the rhythmic expression of a protein called CIRP, and that this molecule is required for a robust activation of clock genes on a daily basis.”

The majority of regulatory proteins bind to the genes directly in order to control the genes expression. However, CIRP binds to gene transcripts, the RNAs.

The team developed a ultra sophisticated genetic engineering technique and found that nearly all CIRP’s target RNAs in living cells. This technique allowed the researchers to probe the transcriptome, RNAs from all genes transcribed at a given time.

Schibler said: “CIRP binds transcripts encoding different circadian oscillator proteins in the cell, which increased their stability and allows them to accumulate.”

The researchers were also able to localize and count each RNA molecule of a targeted circadian gene named Clock.

This system functions a bit like that of a clockwork: temperature variations induce a rhythmic production of CIRP, which in turn reinforces cyclic activation of circadian oscillator genes. In humans, the difference of 1°C in body temperature observed between the morning and the evening takes on new significance.

Schibler explained:

“We have recently demonstrated that such a small fluctuation was sufficient to synchronize cellular oscillators.

One of these biochemical cogs controlled by CIRP induces cyclic accumulation of DBP. Certain anti-tumor drugs administered to sick mice in the morning lead to a 100% mortality, while the rodents receiving the same dose in the evening all survive. This shows how much internal clocks can influence the efficacy and toxicity of drugs.”

Written by Grace Rattue