November 25, 2008

Molecular Basis of Genetic Switch In The Circadian Clock

circadian clock showing PER, CRY proteins, Bmal and clock
It is said that the early bird gets the worm. So what is it that makes them rise early? Scientists have questioned it for long. It was in 1995, David Welsh, then a graduate student, discovered that individual cells dissected out from the 'suprachiasmatic nucleus' of rats' hypothalamus showed spontaneous oscillations. And this set the ball rolling!

All organisms from simple unicellular to humans have their own clock mechanisms. We for example, have not one but many oscillators. The master clock that oversees all the other clocks is located in a part of the brain called hypothalamus, the suprachiasmatic Nucleus or SCN for short. The clock circuit is based on transcription and translation of a genetic switch that resides in the SCN. In the nucleus, a gene, called the Per1 gene,  produces a protein called PER (for period). Like other proteins, its production is regulated by a promoter sequence of DNA, which is known as E-box. A heterodimer (dimer because it consists of two molecules; hetero because the molecular weights/size is different) consisting of proteins BMAL1 (also known as MOP 3) and CLOCK sit atop the E-box sequence. Together they regulate the Per1 gene (other clock genes like AVP or arginine-vasopressin genes are also regulated)  resulting in the production of PER1 protein. So, in a way the E-box may be considered as the genetic switch and the heterodimer of BMAL1 and CLOCK the regulator.

Lets suppose that Per1 gene is producing PER1 protein. So, the concentration of this protein in the cytoplasm will rise. This PER1 protein will now combine with other clock proteins namely, PER2 protein, CRY 1 and 2 proteins (CRY for cryptochrome) in the cytoplasm; and will finally reach the nucleus. In the nucleus, they inhibit the Bmal1 and Clock heterodimer transcription factor, which will lead to a drop in PER production. Thus, the positive feedback of BMAL1 and CLOCK on Per1 gene; and negative feedback of PER and CRY protein on the BMAL1 and CLOCK heterodimer keep the clock running. See the adjoining figure. Other proteins like TIM (timeless) and CK1e (casein kinase 1 epsilon; it degrades PER proteins) may also play some role. New research however suggests that CRY proteins, particularly CRY1 protein is a stronger repressor of the said heterodimer.

Research by Leloup et al showed that the mRNA of Bmal1 was in antiphase with that of Per and Cry. This was expected, because they are negatively correlated. Else both the proteins would peak at the same time and the periodicity would be lost. They also observed that the phase of the spontaneous circadian rhythm did not lock. This is because, circadian rhythm is very flexible. In humans, the cycle repeats about every 24.2 hours. The circadian clock is reset by light and our circadian apparatus is exquisitively sensitive to lights falling on the retina. The retina sends this light (for synchronization) to the SCN via the retino-hypothalamic tract. This synchronization or entrainment can now 'phase lock' the circadian rhythm.

Clinical implication of circadian (circa=about; dian=day) rhythm is enormous. Our sleep-wake cycle, growth hormone and cortisol secretion are only a few example. A person in whom the circadian period is short will rise early (early bird?) and a 'night owl' will have his/her circadian period short. Curiously, our sleepiness, tendency to sleep and occurrence of REM sleep peaks (resulting from endogenous circadian rhythm) when we are about to rise; and our endogenous clock reaches its peak about 1-3 hrs before our habitual bedtime. They say that it is a natural homeostatic mechanism, so that we fell less sleepy as daytime passes on and etc. But I not convinced.

But one thing I am sure to abide by is this that I won't deprive my SCN its daily dose of sunlight. I will also not expose myself to undue light (from computer monitor etc) at night and go to bed at a reasonably fixed time. Fiddling with these may result in insomnia or excessive somnolence as in night shift workers and in jet lag (due to latitude/time-zone changes).

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Reference: BMC Molecular Biology 2008, 9:41 doi:10.1186/1471-2199-9-ResearchBlogging.orgJ.-C. Leloup (2003). Toward a detailed computational model for the mammalian circadian clock Proceedings of the National Academy of Sciences, 100 (12), 7051-7056 DOI: 10.1073/pnas.1132112100

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