24.6:
Circadian Rhythms and Gene Regulation
Nearly all living organisms from microorganisms to mammals synchronize their behavioral, biochemical, and physiological processes according to the 24-hour solar cycle, or the circadian clock.
The circadian clock is primarily controlled by specific machinery, and in mammals, the suprachiasmatic nucleus present in the hypothalamus acts as a master clock and controls circadian rhythms throughout the body.
However, most cells in the body also have an internal circadian rhythm. A cyclic pattern of expression of genes in these cells guides the circadian clock at the organism level.
The underlying genetics of the circadian rhythms at the cellular level have classically been studied in Drosophila, where a set of clock genes regulate the cell circadian rhythm through a negative feedback loop.
During the day time, the transcription factors, Clock and Cycle heterodimerize and activate the transcription of their target genes, including the Period gene, also known as Per.
The Per protein dimerizes with another protein called Timeless, or Tim. However, both these proteins are not very stable in the presence of light and are subsequently degraded by a proteasome.
During the evening, the stable Per/Tim complex can accumulate in the cell cytoplasm and then translocate to the nucleus – where it binds to the Clock-Cycle dimer, and removes it from DNA- thereby, inhibiting its transcriptional activity.
In addition to this negative feedback regulation, other regulatory proteins in the cell also participate in the modulation of the activity of Clock.
For example, Clockwork Orange is a transcriptional repressor that co-represses Clock-cycle transcriptional activity along with Per by competing for the binding site on DNA.
Since circadian rhythms play an essential role in coordinating normal body functioning, any disruption to it can lead to minor to severe diseases, including metabolic syndromes and inflammatory diseases, as well as cancer.
24.6:
Circadian Rhythms and Gene Regulation
The biological clock is involved in many aspects of regulating complex physiology in all animals. It was in 1935 when German zoologists, Hans Kalmus and Erwin Bünning, discovered the existence of circadian rhythm in Drosophila melanogaster. However, the internal molecular mechanisms behind the circadian clock remained a mystery until 1984, when Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered the expression of the Per gene oscillating over a 24-hour cycle. In subsequent years, many other associated genes were identified, and the mechanism of regulation of the circadian rhythms was further unraveled. The contribution of Jeffrey C. Hall, Michael Rosbash, and Michael W. Young to the understanding of the internal biological circadian clocks was recognized with the Nobel Prize for Physiology or Medicine in 2017.
The Molecular Mechanism of Circadian Rhythms
In Drosophila, the Period (PER) protein is the main regulatory protein that controls the internal circadian rhythms in cells. PER forms a complex with another essential protein called Timeless (TIM) and enters the nucleus. Here, it can regulate the levels of PER expression in the cell through feedback inhibition. Additionally, it also controls the expression of other genes by inhibiting the activity of the transcriptional activators Clock and Cycle. Importantly, the stability of the PER/TIM complex is dependent on the presence or absence of light, meaning it is degraded under daytime conditions. The result is that the expression of genes downstream of the PER/TIM complex is controlled by light, and this phenomenon allows for synchronization of the circadian clock.
In mammals, the regulation of the circadian rhythm works in a very similar manner. However, due to the addition of several paralog genes, the regulation of the entire pathway is much more complicated than in Drosophila.
Significance of Circadian Rhythms
All living organisms on Earth have evolved in the presence of 24-hour day/night cycles and adapted their cellular, physiological as well as behavioral responses accordingly. For example, the diurnal cycles of sleeping and waking, body temperature, and hormone release in mammals are controlled by the circadian rhythms. Irregular circadian rhythms can lead to many health issues, such as bipolar disorder or sleep disorders. Additionally, disruption of circadian rhythms can result in adverse effects on other systems of the body, including the cardiovascular system.
Suggested Reading
- Andreani T.S. et al. Genetics of Circadian Rhythms. Sleep Med Clin. 10(4): 413–421 (2015). doi:10.1016/j.jsmc.2015.08.007.