Life originated on Earth first because of light, as we discussed last week (How Did Protein Synthesis Originate?). Life originated in the presence of Earth's day and night cycles that most present-day organisms (from bacteria to plants to animals) come equipped with a rich internal clock system that dictates many different behaviors at different times of the day.

These vital on-board life support systems allow organisms to take cues from their environment and anticipate the appropriate action before it happens, suppose it's similar to carrying your banking card with you before leaving home. One might expect this to be complex system of moving parts, perhaps something similar to a Grandfather clock. However, as it turns out that, which is true for almost all of life, including humans, these timekeepers are the work of a specialized group of cells called suprachiasmatic nucleus (SCN) cells. In humans, they are located in the hypothalamus. In Drosophila, where much of the genomic research has centered, shows circadian cycles occuring within the thorax, abdomen, antenna, legs, wings, and testis. When placed in lab culture, these cells operate independently from one another, similar to the cultured effects of SCN cells in humans. The sustainability of each cell can be reset according to light and dark cycles externally [2]. Following more drastic shifts, as anyone who has experienced jet lag knows, these cycles gradually shift to their new cycles of light and dark.

Research Impact - Circadian Rhythms Based on Feedback in Gene Regulation

Understanding how these circadian clocks tick is one of the fundamental endeavors in cell biology for there are still many details understand only vaguely. Studies in a variety of organisms have revealed the molecular processes and basic principles underpinning each component. Physiology is, obviously, more complex than what the brochure for life says, which mine stated clearly life is a, phenomenon of light. Other factors are of course involved, such as temperature, nutrition, metabolism, and other factors that would affect an organism's homeostasis. The clock must also be able to be function in the presence of multiple inputs and reset according to changes in the environment. This pacemaker of life keeps the organsism in sync with its environment.

The part of the circadian clock that has been well documented comes mostly from work performed by genotyping the Drosophila fly. Drosophila use a rather simple method of time-keeping, a kind of metronome that works on a time-delay. When certain key factors are present, transcription turns off. When those factors disappear transcription clicks back on, shown below in Figure 1.

Figure 1. Map of Drosophila's circadian clock mechanism

figure-1per.timfeedbackloop

Model of the Per/Tim feedback loop. The central feature of the clock mechanism is the accumulation and decay of two regulatory proteins, Tim (short for timeless) and Per (short for period). These proteins are translated in the cytosol, until at a certain point, they reach critical concentration and they form a heterodimer. This heterodimer is then able to pass into the nucleus of the cell where it regulates a concert of genes that keeps the cell in time with the circadian clock. Although most of the cells in Drosophila are not considered true photoreceptors, they do sense the light because of specialized flavoproteins that causes the rapid destruction of the Tim protein, thus resetting the clock. From Hardin (2005) Current Biology 15:R714-R722.

For mammals the process is similar as the Journal of Biological Rhythms reported in one article, Core clock components are defined as genes whose protein products are necessary for the generation and regulation of circadian rhythms within individual cells throughout the organism [3].

Clinical Impact

Recent studies have revealed that the circadian clock is cell-autonomous and self-sustained not only in the SCN but also in peripheral tissues and in dissociated cultured cells [4].

"Circadian clocks influence nearly all aspects of physiology and behavior, including rest wake cycle, cardiovascular activity, hormone secretion, body temperature and metabolism. Recently, a familial sleep disorder in humans has been linked to mutations in human circadian genes Per2 and CK1δ (25,29). This behavioral trait is known as FASPS, and the patients exhibit early sleep onset followed by early-morning awakening (53). In contrast, delayed sleep phase syndrome (DSPS) patients show sleep-onset insomnia with an inability to awake at a conventional time in relation to the general public.

Genetic studies suggest that DSPS is associated with a specific haplotype of human Per3 gene (54,55). These findings indicate involvement of the clock genes in the susceptibility to sleep disorders, and altered sleep homeostasis has been observed in various circadian mutant mice.

Considerable insight into the role of circadian timing in biological processes has been gained from gene profiling studies. Microarray results from different tissues in the wild-type and mutant mice support the tissue-dependent circadian gene expression patterns (60,63). Circadian genes are expressed in a tissue-specific manner with only a minor overlap of cycling transcripts between tissues. For example, when the sets of cycling transcripts are compared between the SCN and liver, only ~10% are common to both (60,62). This is also seen in other comparisons of different tissues (61). Furthermore, a significant number of the transcripts that express in both tissues cycle in only one of the tissues and not in the other, and different circadian transcripts within one tissue can accumulate with varying phases.

The identification of the circadian transcripts has revealed that the transcriptional circadian regulation extends beyond core clock components to include various clock-controlled genes (CCGs), including key regulators for cell cycle and metabolism (60,61).

Overall, circadian regulation in peripheral tissues is important to maintain normal cellular functions, and a disruption of core clock genes can be damaging to the organism's overall well-being (64,66)."

Are circadian rhythyms tied to Inheritance?

Cell memory is essential to the development and sustainability of cells. Positive feedback loops provide the simple strategy for cell memory, generally speaking, but that means they also form the basis of establishing patterns of gene expression that become the inheritable traits of gene transcription. One theory holds that early molecules evolved to become self-sufficient based upon limited resources and inputs of light and dark. Once these early patterns of expression were established, these regulatory genes then experimented with different arrangments that would help maintain its genetic code.

Figure 2. How positive feedback loops create cell memory

inheritedpositivefeedbackloop

Protein A is a gene regulatory protein that activtes its own transcription. All of the descendants of the original cell had experienced a self-sustaining feedback loop based on transient signals, the presence of the gene's products that sustain the gene's activity. {Image source: NCBI, http://www.ncbi.nlm.nih.gov/books/NBK28289/}

So while the positive feedback loop promotes a self-sustaining transcription mechanism, another set of genes must repress the transcription of other gene regulatory proteins. In this way, circadian clocks function through negative feedback control, with programmed delays operating roughly on a ~24 hour cycle (some more some less) [source]. By packing its own sundial, individual cells become the repository of environmental cues that allow the organsim to take the appropriate behavioral action. Together these mechanisms operate in tandem each with its own pattern of gene expression creating the stage for the inhertence of some sophisticated traits. It would not be at all unrighteous to consider this one of life's primary achievements toward self-sustainability.

The original gene-circuit is theought to have a sleek, simple design, which allowed them to be combined and rearranged only to be assembled and reassembled into other control devices. Then one day, these genes would band together to form an entire genetic circuitboard for the organism to use (be it plants or animals, bacteria or fungus). From this vantage point, it is possible to consider how such complex regulatory circuits have combined to one form. Not only is the system complex, the programming comes unified and works cooperatively within a chaotic internal environment, created from each set of gene expression proteins. It is complex, and the most logical way of operation.

A.G. Scientific likens our gene regulatory proteins to the words of a language. Each word bears a different meaning, can be used in a variety of contexts, with different combinations, rarely ever used alone. Language can be similar to chemistry in that it's the right combination of words that conveys the information, either a memory, historical fact, or event that otherwise provides a context to even assemble a message from the available words. We cherish that each one of our products is unique, and delivers exactly that which keeps language moving, influential, and alive!

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Recommended Review Articles

[1] Lowrey P.L., Takahashi J.S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization.Annual Review Genomics Human Genetics. (2004). 5:407-441.

[2] Reppert S.M., Weaver D.R. Coordination of circadian timing in mammals. Nature. (2002). 418:935-94.

[3] Takahashi J.S. Finding new clock components: past and future. Journal Biological Rhythms. (2004). 19:339-347.

[4] Hardin, P. E. (2005). The circadian timekeeping system of Drosophila. Current Biology 15:R714-R722.