Circadian Rhythm


In light-sensitive higher organisms, the biological clock is a set of functional systems formed by photoreceptor neurons, endocrine systems, and gene timing oscillation expression regulation. It enables the organism to form a rhythm of day and night from microscopic levels of gene expression, cell metabolism, and macroscopic biological behavior.

As a manifestation of the biological clock, the formation of the circadian rhythm in the biological clock is mainly affected by two factors: 1. Correction of the clock; 2. Cycle of the clock. Similar to a normal clock, the circadian clock has a correction mechanism. In the human brain, the suprachiasmatic nucleus is the master clock, which is responsible for integrating the perceived external light signals and transmitting information to the peripheral clocks of the body. This central clock is proofread every day, and the proofreading is based on light. Since the calibration is performed once every day and night, the cycle of this clock is 24 hours.

In addition to the optic nerve, other cells in the body do not have the ability to sense light and therefore need to be operated by the command of the central clock. Because the central clock can receive the signal from the optic nerve, and can transmit the signal from the center to the place, so that the various cells and organs of the body can work together in concert. Among them, the endocrine system plays a role in transmitting signals by secreting hormones in this process. Different hormones have the function of transmitting different signals.

Molecular Mechanism

When the cell receives a signal during the day, it initiates an ordered set of gene expression programs accordingly. Under the induction of daytime light signals, the expression of certain genes (genes associated with daytime activities) is more advantageous, and the function of night-related genes is inhibited. Because of the importance of circadian rhythms to living organisms, a central clock is needed to adjust the pace of the day and night genes to alternate, making them consistent. For example, the study found that the PER and CRY genes are dominant genes expressed during the day. In insects, CRY (Cryptochrome) can sense blue light. Like the PER (Period) gene, it expresses very low at the end of the night, at the beginning of the day, then gradually rises, and reaches its peak at the end of the night. During this process, CLOCK and BMAL1 proteins are involved in the regulation of PER and CRY gene expression. They promote their expression by binding to the E-box region of the PER and CRY gene promoters. Interestingly, although CLOCK and BMAL1 proteins promote the expression of PER and CRY, the expression of PER and CRY in turn inhibits the function of CLOCK and BMAL1 proteins. When it is just entering the night, the PER and CRY proteins with peak expression will form dimers and enter the nucleus, inhibit CLOCK and BMAL1 functions, and then inhibit the expression of PER and CRY. At the same time, PER and CRY are slowly degraded due to their inherent instability. Therefore, the amount of PER will gradually decrease as the night darkens, and at the end of the night and at the beginning of the day, it will return to the beginning of the entire cycle. As a result of the decrease in PER and CRY content, inhibition of CLOCK and BMAL1 is removed, and new PER and CRY are re-transcribed. As a result, a negative feedback system with periodic oscillations is formed.

Figure 1. The mechanism of circadian rhythm.

In addition to the PER, CRY, CLOCK and BMAL1 mentioned above, important regulators of the biological clock include TIM (Timeless) and DBT (Doubletime). In Drosophila, TIM is also regulated by CLOCK and CYCLE (corresponding to BMAL1 in mammals). When TIM is transcribed and translated into protein, it forms a complex with PER and prevents PER from being degraded. At the same time, this complex can also enter the nucleus, inhibiting the function of CLOCK and CYCLE. TIM is a protein that can be degraded by light signals. The process is realized by the photoreceptor protein CRY. Therefore, the light can remove the protection of the PER, so that the PER will be slowly degraded after the TIM is degraded. DBT (called CKI in mammals) is a factor that promotes PER degradation. When TIM and PER are combined, DBT cannot degrade PER because it cannot combine with PER. When the TIM is degraded by the light-stimulated signal, the PER is exposed from the complex and can be phosphorylated by DBT to be degraded. In mammals, DBT promotes nuclear transfer of PER and allows PER to inhibit CLOCK and BMAL1 in the nucleus.

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