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.