Tracking Jet Lag to the Source
Researchers from Freie Universität describe a new mechanism to control the body’s internal clock
Jul 02, 2014
A team of researchers headed by biochemistry professor Florian Heyd of Freie Universität Berlin has succeeded in controlling the circadian clock – the body’s internal sense of time – in mice in such a way that the animals adjust more quickly to different time zones. The members of the RNA biochemistry research group were able to show that the “alternative” splicing of a certain gene controls how the lab animals adjust to different time zones.
Without this gene, the animals adjust without needing any extra time to re-acclimate themselves – the phenomenon known as jet lag. Splicing is the process in which the initially formed pre-mRNA is modified into mature mRNA, the intracellular information carrier.
Alternative splicing allows cells to respond to changes in external influences by forming different mRNA from a single pre-mRNA transcript. These findings can probably also be applied to humans, and they are relevant in particular because disruptions in the circadian rhythm can promote diseases such as metabolic disorders and cancer. The study has now been published by the researchers from Freie Universität. Entitled “Rhythmic U2af26 Alternative Splicing Controls PERIOD1 Stability and the Circadian Clock in Mice,” it forms the basis for further work examining these kinds of connections. The study was published in the journal Molecular Cell on May 15, 2014.
All life forms, from bacteria to humans, follow an internal rhythm that controls fundamental functions. For example, metabolism, physical and mental performance capacity, and even immune system activity are subject to cyclical fluctuations. This rhythm is controlled by external influences – in humans, mainly light. Various bodily functions are synchronized by a central clock located in a tiny area of the brain called the suprachiasmatic nucleus. The circadian clock is slow to adjust to sudden changes in the rhythm of light and dark, which is what causes jet lag when people travel from one time zone to another.
Florian Heyd and members of his research group have now been able to describe for the first time a new mechanism generating pulses in the body’s internal clock: Adjustment to a different time zone is controlled through alternative splicing of the U2AF26 gene. This mechanism takes advantage of the fact that the protein-coding segments (exons) of a gene in our DNA – the carrier of genetic information – are not present in a single contiguous piece, but instead are spliced together only after transcription, during a process of further processing.
Cells can react to external influences through alternative splicing of certain exons. This means, for example, that these exons are no longer included in the messenger RNA (mRNA).
This is exactly what happens with the U2AF26 gene in mice under jet lag conditions. Alternative splicing of two exons after the light conditions change alters the pulse sequence of the mRNA, forming a changed protein. This protein then regulates the circadian clock and the shift to a new time zone directly.
Both the mechanism – formation of a new protein through a different pulse sequence in the mRNA – and the result, control of the circadian rhythm through alternative splicing in a mammal, are groundbreaking discoveries that will now serve as the basis for further research. For example, a disruption in circadian rhythm can lead to the development of various diseases, such as metabolic disorders and cancer. “Now we want to study whether alternative splicing of the U2AF26 gene is involved in these processes in humans, thereby contributing to a better molecular understanding of these diseases,” Heyd says. He adds, “Beyond that, we are also looking for additional genes that are regulated by a similar mechanism, controlling other cellular functions in this way.”
Prof. Dr. Florian Heyd, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Tel.: +49 30 838-62938, Email: firstname.lastname@example.org
Preußner et al., Rhythmic U2af26 Alternative Splicing Controls PERIOD1 Stability and the Circadian Clock in Mice, Molecular Cell (2014), DOI: http://dx.doi.org/10.1016/j.molcel.2014.04.015