3.6
昼夜节律和基因调控
生物钟涉及调节所有动物复杂生理机能的许多方面。 1935 年，德国动物学家 Hans Kalmus 和 Erwin Bünning 发现果蝇存在昼夜节律。 然而，生物钟背后的内部分子机制一直是个谜，直到 1984 年 Jeffrey C. Hall、Michael Rosbash 和 Michael…
从微生物到哺乳动物，几乎所有生物体都会根据24小时的太阳周期（即昼夜节律钟）来同步其行为、生化和生理过程。
昼夜节律主要由特定的分子机制调控，在哺乳动物中，下丘脑中存在的视交叉上核作为主时钟，调控全身的昼夜节律。
然而，人体内的大多数细胞也具有内在的昼夜节律。这些细胞中基因表达的周期性模式在生物体水平上调控着昼夜节律钟。
在细胞水平上，昼夜节律的遗传基础传统上是在果蝇（Drosophila）中进行研究的，其中一组时钟基因通过负反馈环路调控细胞的昼夜节律。
在白天，转录因子 Clock 和 Cycle 形成异源二聚体，并激活其靶基因的转录，其中包括被称为 Per 的Period基因。
Per蛋白会与另一种称为Timeless（Tim）的蛋白形成二聚体。然而，这两种蛋白在光照条件下均不稳定，随后会被蛋白酶体降解。
在夜间，稳定的Per/Tim复合物可在细胞质中积累，随后转入细胞核，与Clock-Cycle二聚体结合，并使其脱离DNA，从而抑制其转录活性。
除了这种负反馈调节外，细胞中的其他调节蛋白也参与调控 Clock 的活性。
例如，Clockwork Orange 是一种转录抑制因子，通过与 Per 竞争 DNA 上的结合位点，共同抑制 Clock-cycle 的转录活性。
由于昼夜节律在协调正常机体功能中起着至关重要的作用，任何对其的干扰都可能导致从轻微到严重的多种疾病，包括代谢综合征和炎症性疾病，以及癌症。
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Q1: How do Clock and Cycle proteins control circadian gene expression during the day?
During daytime, Clock and Cycle proteins heterodimerize and activate transcription of target genes, including the Period gene. This transcriptional activity drives the expression of Per and other clock-controlled genes. The Clock-Cycle complex acts as the primary transcriptional activator in the circadian signaling pathway and mechanism.
Q2: What role does the Per/Tim complex play in circadian rhythm regulation?
The Per protein dimerizes with Timeless to form a stable complex that accumulates in the cytoplasm during evening hours. This Per/Tim complex translocates to the nucleus and binds to the Clock-Cycle dimer, inhibiting its transcriptional activity. This negative feedback loop is essential for maintaining the 24-hour circadian cycle.
Q3: How does light affect the stability of circadian clock proteins?
Per and Timeless proteins are unstable in the presence of light and are degraded by the proteasome during daytime. This light-dependent degradation prevents Per/Tim complex accumulation during the day, allowing Clock-Cycle to remain active. The stability of these proteins depends on the absence of light, enabling circadian synchronization with the solar cycle.
Q4: What is the function of Clockwork Orange in circadian regulation?
Clockwork Orange is a transcriptional repressor that co-represses Clock-Cycle activity alongside Per by competing for DNA binding sites. This additional regulatory layer provides fine-tuning of circadian gene expression. Multiple regulatory proteins work together to modulate Clock activity and maintain precise circadian timing.
Q5: Where is the master circadian clock located in mammals?
In mammals, the suprachiasmatic nucleus located in the hypothalamus acts as the master clock controlling circadian rhythms throughout the body. However, most cells in the body also possess their own internal circadian rhythms. These cellular clocks are coordinated by the suprachiasmatic nucleus to synchronize organism-level physiological and behavioral processes.
Q6: What health consequences result from disrupted circadian rhythms?
Disruption of circadian rhythms can lead to metabolic syndromes, inflammatory diseases, and cancer. Irregular circadian rhythms also cause sleep disorders and bipolar disorder. Additionally, circadian disruption adversely affects the cardiovascular system and other body systems, demonstrating the importance of maintaining proper circadian synchronization.
Q7: Why were Jeffrey Hall, Michael Rosbash, and Michael Young awarded the Nobel Prize in 2017?
These scientists discovered the molecular mechanisms of circadian rhythms, including the oscillating expression of the Period gene over a 24-hour cycle. Their work revealed how clock genes regulate cellular circadian rhythms through feedback loops. Their discoveries transformed understanding of the internal biological clock and earned them the 2017 Nobel Prize in Physiology or Medicine.