The Circadian Molecular Clock

Have you ever woken up before the alarms went off and wondered why? It is as if your body is wired with an internal clock. The whole living system, from humans to animals to plants and single cells are controlled by an internal timekeeper, called the circadian clock, to keep its system on schedule. The word circadian comes from the Latin word circa which translates “approximately” and diem, “day”. We humans depend on our internal clock to regulate our body’s physiological and behavioral rhythms. The internal clock would dictate the time of day where we feel sleepy, energized, hungry and biological functions such as blood pressure, metabolism, body temperature and hormone release. Whereas, in other organisms, the circadian clocks would help them navigate the daily transitions between light and darkness.

In humans, the circadian clock is primarily set to ~24 hours. However, it can be reset by external factors, especially light. The ability of our internal clock to synchronize to the natural 24-hour day is called environmental entrainment. Thus, a person who travels to a new time zone, would be able to acclimatize after a few days of adjustments. The body’s master clock consists of about 20,000 neurons that form a structure called the suprachiasmatic nucleus (SCN). The SCN is located in the hypothalamus of the brain that receives direct input of signals from the eyes. This structure regulates the release of melatonin, a hormone that is produced in response to darkness to calm the body in preparation for sleep. Under usual circumstances, the brain produces more melatonin at night – when there is less light. Nevertheless, scientists are investigating the potential of light exposure from digital devices (during the night) in altering the circadian patterns and sleep-wake cycles.

Hence, this poses the idea that the circadian clock must have some basis on the molecular level, presenting questions:

a) How do individual cells in animals and plants (let alone bacteria) know what time it is?
Generally, this is possible because the circadian clock is controlled by a genetic feedback loop, where proteins regulate gene expression with 24-hour periodicity. The clock proteins exhibit negative feedback which would in turn repress the transcription-translation of clock genes that produce the proteins. The production of clock proteins will continue till it reaches a threshold, at which the production will cease. However, these proteins are short-lived and would degrade at a regular rate. The proteins would decrease to a level in which gene expression could resume, repeating the cycle. Remarkably, the expression and degradation rates have been so fine-tuned by evolution that it matches a 24-hour day!

b) Is there a certain “clock gene”?
Scientists have been researching on organisms with similar biological genes, including fruit flies and mice as study models. Experiments were studied by altering the environmental parameters to different light and dark periods to investigate the change in gene activities and molecular signals. Organisms with irregularities were also studied to identify the genetic components that may have “broken” the internal clock. For instance, in the early 1970s, Ron Konopka and Seymour Benzer identified abnormal circadian patterns in mutant Drosophila flies and traced the flies’ mutations to a single gene, period (per). The discovery spearheaded the molecular studies of the clock genes in the mammalian/mice system as the per gene was found to exhibit a circadian rhythm. In addition to sharing a common feature of the PAS domain with the Drosophila PER, the CLOCK protein and its binding partner, BMAL1 have bHLH domains that allow DNA to directly bind to regulatory elements on rhythmic genes to modulate their transcription. As irregularities in pattern have shown to be linked to various chronic health conditions such as sleep disorders, obesity, diabetes, depression and bipolar disorder, many more circadian genes are being discovered today; these genes, having names like timeless, clock, and cycle, orchestrate the behavior of hundreds of other genes and display a high degree of evolutionary conservation across species.

Figure: Molecular mechanism of the circadian clock in – (a) Drosophila flies and (b) mammalian system. Heterodimer of two bHLH-PAS domain-containing transcription factors, dCLK and CYC (Drosophila) binds to the E-box (regulatory element) in per and tim; CLOCK and BMAL1 (mammalian) in Per and Cry promoters,initiating transcription.

As a takeaway, understanding the factors that contribute to the disruption of our biological clocks will pave ways to treatment for sleep disorders, obesity, mental health disorder, jet lag and other health problems. It can also shed light to individuals in understanding the biological systems of the human body or even ways to adjust to night shift work!

Reference (Sept-20-A6)

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