Oscillating gene

Last updated August 13, 2023

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles.^[1]^[2] Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms.^[3] Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.^[4]

History

The first recorded observations of oscillating genes come from the marches of Alexander the Great in the fourth century B.C.^[5] At this time, one of Alexander's generals, Androsthenes, wrote that the tamarind tree would open its leaves during the day and close them at nightfall.^[5] Until 1729, the rhythms associated with oscillating genes were assumed to be "passive responses to a cyclic environment".^[3] In 1729, Jean-Jacques d'Ortous de Mairan demonstrated that the rhythms of a plant opening and closing its leaves continued even when placed somewhere where sunlight could not reach it. This was one of the first indications that there was an active element to the oscillations. In 1923, Ingeborg Beling published her paper "Über das Zeitgedächtnis der Bienen" ("On the Time Memory of Bees") which extended oscillations to animals, specifically bees^[6] In 1971, Ronald Konopka and Seymour Benzer discovered that mutations of the PERIOD gene caused changes in the circadian rhythm of flies under constant conditions. They hypothesized that the mutation of the gene was affecting the basic oscillator mechanism.^[7] Paul Hardin, Jeffrey Hall, and Michael Rosbash demonstrated that relationship by discovering that within the PERIOD gene, there was a feedback mechanism that controlled the oscillation.^[8] The mid-1990s saw an outpouring of discoveries, with CLOCK, CRY, and others being added to the growing list of oscillating genes.^[9]^[10]

Molecular circadian mechanisms

The primary molecular mechanism behind an oscillating gene is best described as a transcription/translation feedback loop.^[11] This loop contains both positive regulators, which increase gene expression, and negative regulators, which decrease gene expression.^[12] The fundamental elements of these loops are found across different phyla. In the mammalian circadian clock, for example, transcription factors CLOCK and BMAL1 are the positive regulators.^[12] CLOCK and BMAL1 bind to the E-box of oscillating genes, such as Per1, Per2, and Per3 and Cry1 and Cry2, and upregulate their transcription.^[12] When the PERs and CRYs form a heterocomplex in the cytoplasm and enter the nucleus again, they inhibit their own transcription.^[13] This means that over time the mRNA and protein levels of PERs and CRYs, or any other oscillating gene under this mechanism, will oscillate.

There also exists a secondary feedback loop, or 'stabilizing loop', which regulates the cyclic expression of Bmal1.^[12] This is caused by two nuclear receptors, REV-ERB and ROR, which suppresses and activates Bmal1 transcription, respectively.^[12]

In addition to these feedback loops, post-translational modifications also play a role in changing the characteristics of the circadian clock, such as its period.^[13] Without any type of feedback repression, the molecular clock would have a period of just a few hours.^[12] Casein kinase members CK1ε and CK1δ were both found to be mammalian protein kinases involved in circadian regulation.^[12] Mutations in these kinases are associated with familial advanced sleep phase syndrome (FASPS).^[14] In general, phosphorylation is necessary for the degradation of PERs via ubiquitin ligases.^[15] In contrast, phosphorylation of BMAL1 via CK2 is important for accumulation of BMAL1.^[16]

Examples

The genes provided in this section are only a small number of the vast amount of oscillating genes found in the world. These genes were selected because they were determined to be the some of most important genes in regulating the circadian rhythm of their respective classification.

Mammalian genes

Cry1 and Cry2 – Cryptochromes are a class of blue light sensitive flavoproteins found in plants and animals. Cry1 and Cry2 code for the proteins CRY1 and CRY2. In Drosophila, CRY1 and CRY2 bind to TIM, a circadian gene that is a component of the transcription-translation negative feedback loop, in a light dependent fashion and blocks its function. In mammals, CRY1 and CRY2 are light independent and function to inhibit the CLOCK-BMAL1 dimer of the circadian clock which regulates cycling of Per1 transcription.^[17]
Bmal1 – Bmal1 also known as ARNTL or Aryl hydrocarbon receptor nuclear translocator-like, encodes a protein that forms a heterodimer with the CLOCK protein. This heterodimer binds to E-box enhancers found in the promoter regions of many genes such as Cry1 and Cry2 and Per1-3, thereby activating transcription. The resulting proteins translocate back into the nucleus and act as negative regulators by interacting with CLOCK and/or BMAL1 inhibiting transcription.^[11]
Clock – Clock, also known as Circadian Locomotor Output Cycles Kaput, is a transcription factor in the circadian pacemaker of mammals. It affects both the persistence and period of circadian rhythms by its interactions with the gene Bmal1. For more information, refer to Bmal1.
Per genes – There are three different per genes, also known as Period genes, (per 1, per 2, and per 3) that are related by sequence in mice. Transcription levels for mPer1 increase in the late night before subjective dawn and is followed by increases in the levels of mPer3 and then by mPer2. mPer1 peaks at CT 4-6, mPer3 at CT 4 and 8 and mPer2 at CT 8.^[18] mPer1 is necessary for phase shifts induced by light or glutamate release.^[19] mPer 2 and mPer3 are involved in resetting the circadian clock to environmental light cues.^[20]

Drosophila genes

Clock – The clock gene in Drosophila encodes for the CLOCK protein and forms a heterodimer with the protein CYCLE in order to control the main oscillating activity of the circadian clock.^[21] The heterodimer binds to the E-box promoter region of both per and tim which causes activation of their respective gene expression. Once protein levels for both PER and TIM have reached a critical point, they too dimerize and interact with the CLOCK-CYCLE heterodimer to prevent it from binding to the E-Box and activating transcription. This negative feedback loop is essential for the functioning and timing of the circadian clock.^[22]
Cycle – the cycle gene encodes for the CYCLE protein to form a heterodimer with the protein CLOCK. The heterodimer creates a transcription-translation feedback loop that controls the levels of both the PER and TIM gene. This feedback loop has been shown to be imperative for both the functioning and timing of the circadian clock in Drosophila. For more information, refer to Clock.^[21]
Per – The per gene is a clock gene that encodes for the PER protein in Drosophila. The protein levels and transcription rates of PER demonstrate robust circadian rhythms that peak around CT 16. It creates a heterodimer with TIM to control the circadian rhythm. The heterodimer enters the nucleus in order to inhibit the CLOCK-CYCLE heterodimer which acts as a transcriptional activator for per and tim. This results in an inhibition of the transcription factors of per and tim thereby lowering the respective mRNA levels and protein levels.^[23] For more information, refer to Clock.
Timeless – The tim gene encodes for the TIM protein that is critical in circadian regulation in Drosophila. Its protein levels and transcription rates demonstrate a circadian oscillation that peaks at around CT 16. TIM binds to the PER protein to create a heterodimer whose transcription-translation feedback loop controls the periodicity and phase of the circadian rhythms. For more information, refer to Period and Clock.^[8]

Fungal genes

Frq – The Frq gene, also known as the Frequency gene, encodes central components of an oscillatory loop within the circadian clock in Neurospora . In the oscillator's feedback loop, frq gives rise to transcripts that encode for two forms of the FRQ protein. Both forms are required for robust rhythmicity throughout the organism. Rhythmic changes in the amount of frq transcript are essential for synchronous activity, and abrupt changes in frq levels reset the clock.^[18]

Bacterial genes

Kai genes – Found in the Synechococcus elongatus, these genes are essential components of the cyanobacterium clock, the leading example of bacterial circadian rhythms. Kai proteins regulate genome wide gene expression. The oscillation of phosphorylation and dephosphorylation of KaiC acts as the pacemaker of the circadian clock.^[24]

Plant genes

CCA1 – The CCA1 gene, also known as Circadian and Clock Associated Gene 1, is a gene that is especially important in maintaining the rhythmicity of plant cellular oscillations. Overexpression, results in the loss of rhythmic expression of clock controlled genes (CCGs), loss of photoperiod control, and loss of rhythmicity in LHY expression. See LHY gene below for more information.^[18]
LHY – The LHY gene, also known as the Late Elongated Hypocotyl gene, is a gene found in plants that encodes components of mutually regulatory negative feedback loops with CCA1 in which overexpression of either results in dampening of both of their expression. This negative feedback loop affects the rhythmicity of multiple outputs creating a daytime protein complex.^[18]
Toc1 gene – Toc1, also known as Timing of CAB Expression 1 gene, is an oscillating gene found in the plants that is known to control the expression of CAB. It has been shown to affect the period of circadian rhythms through its repression of transcription factors. This was found through mutations of toc1 in plants that had shortened period of CAB expression.

Related Research Articles

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is the principle circadian pacemaker in mammals and is necessary for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow the SCN to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (per^S), lengthen (per^L), and even abolish (per⁰) the period of the circadian rhythm.

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

The PER1 gene encodes the period circadian protein homolog 1 protein in humans.

Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the ARNTL gene on chromosome 11, region p15.3. It's also known as BMAL1, MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

The frequency (frq) gene encodes the protein frequency (FRQ) that functions in the Neurospora crassa circadian clock. The FRQ protein plays a key role in circadian oscillator, serving to nucleate the negative element complex in the auto regulatory transcription-translation negative feedback-loop (TTFL) that is responsible for circadian rhythms in N. crassa. Similar rhythms are found in mammals, Drosophila and cyanobacteria. Recently, FRQ homologs have been identified in several other species of fungi. Expression of frq is controlled by the two transcription factors white collar-1 (WC-1) and white collar-2 (WC-2) that act together as the White Collar Complex (WCC) and serve as the positive element in the TTFL. Expression of frq can also be induced through light exposure in a WCC dependent manner. Forward genetics has generated many alleles of frq resulting in strains whose circadian clocks vary in period length.

Doubletime (DBT) also known as discs overgrown (DCO) is a gene that encodes the double-time protein (DBT) in fruit flies. The gene was first identified and characterized in 1998 by Michael Young and his team at Rockefeller University.

Timing of CAB expression 1 is a protein that in Arabidopsis thaliana is encoded by the TOC1 gene. TOC1 is also known as two-component response regulator-like APRR1.

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

KaiC is a gene belonging to the KaiABC gene cluster that, together, regulate bacterial circadian rhythms, specifically in cyanobacteria. KaiC encodes for the KaiC protein, which interacts with the KaiA and KaiB proteins in a post-translational oscillator (PTO). The PTO is cyanobacteria master clock that is controlled by sequences of phosphorylation of KaiC protein. Regulation of KaiABC expression and KaiABC phosphorylation is essential for cyanobacteria circadian rhythmicity, and is particularly important for regulating cyanobacteria processes such as nitrogen fixation, photosynthesis, and cell division. Studies have shown similarities to Drosophila, Neurospora, and mammalian clock models in that the kaiABC regulation of the cyanobacteria slave circadian clock is also based on a transcription translation feedback loop (TTFL). KaiC protein has both auto-kinase and auto-phosphatase activity and functions as the circadian regulator in both the PTO and the TTFL. KaiC has been found to not only suppress kaiBC when overexpressed, but also suppress circadian expression of all genes in the cyanobacterial genome.

Paul Hardin is a prominent scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Jay Dunlap is an American chronobiologist and photobiologist who has made significant contributions to the field of chronobiology by investigating the underlying mechanisms of circadian systems in Neurospora, a fungus commonly used as a model organism in biology, and in mice and mammalian cell culture models. Major contributions by Jay Dunlap include his work investigating the role of frq and wc clock genes in circadian rhythmicity, and his leadership in coordinating the whole genome knockout collection for Neurospora. He is currently the Nathan Smith Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. He and his colleague Jennifer Loros have mentored numerous students and postdoctoral fellows, many of whom presently hold positions at various academic institutions.

In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.

Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

References

↑ Tuttle, LM; Salis, H; Tomshine, J; Kaznessis, YN (2005). "Model-Driven Designs of an Oscillating Gene Network". Biophys. J. 89 (6): 3873–83. Bibcode:2005BpJ....89.3873T. doi:10.1529/biophysj.105.064204. PMC 1366954 . PMID 16183880.
↑ Moreno-Risueno, Miguel; Benfey, Phillip N. (2011). "Time-based patterning in development: the role of oscillating gene expression" (PDF). Landes Bioscience. 2 (3): 124–129. doi:10.4161/trns.2.3.15637. PMC 3149689 . PMID 21826283.
1 2 Moore, Martin C, Frank M Sulzman, and Charles A Fuller. The Clocks that Time Us: Physiology of the Circadian Timing System. Harvard University Press.
↑ Buhr, ED; Takahashi, JS (2013). "Molecular Components of the Mammalian Circadian Clock". Acta Oto-Laryngologica. Handbook of Experimental Pharmacology. 109 (5–6): 406–15. doi:10.3109/00016489009125162. PMID 2360447.
1 2 Von Dr. Hugo Bretzl.'Botanische Forschungen des Alexanderzuges.' Leipzig: Teubner. 1903
↑ Beling, Ingeborg (1929). "Über das Zeitgedächtnis der Bienen". Zeitschrift für Vergleichende Physiologie. 9 (2): 259–338. doi:10.1007/BF00340159. S2CID 39544233.
↑ Konopka, RJ; Benzer, Seymour (1971). "Clock Mutants of Drosophila melanogaster". Proceedings of the National Academy of Sciences. 68 (9): 2112–2116. Bibcode:1971PNAS...68.2112K. doi: 10.1073/pnas.68.9.2112 . PMC 389363 . PMID 5002428.
1 2 Hardin, P.E.; Hall, J.C.; Rosbash, M. (1990). "Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels". Nature. 343 (6258): 536–40. Bibcode:1990Natur.343..536H. doi:10.1038/343536a0. PMID 2105471. S2CID 4311836.
↑ Thompson CL, Sancar A (2004). "Cryptochrome: Discovery of a Circadian Photopigment". In Lenci F, Horspool WM. CRC handbook of organic photochemistry and photobiology. Boca Raton: CRC Press. pp. 1381–89. ISBN 0-8493-1348-1.
↑ King, DP; Zhao, Y; Sangoram, AM; Wilsbacher, LD; Tanaka, M; Antoch, MP; Steeves, TD; Vitaterna, MH; Kornhauser, JM; Lowrey, PL; Turek, FW; Takahashi, JS (1997). "Positional Cloning of the Mouse Circadian Clock Gene". Cell. 89 (4): 641–653. doi:10.1016/S0092-8674(00)80245-7. PMC 3815553 . PMID 9160755.
1 2 Reppert, Steven M.; Weaver, David R. (2002). "Coordination of circadian timing in mammals". Nature. 418 (6901): 935–941. Bibcode:2002Natur.418..935R. doi:10.1038/nature00965. PMID 12198538. S2CID 4430366.
1 2 3 4 5 6 7 Kwon, I.; Choe, HK; Son, GH; Kyungjin, K (2011). "Mammalian Molecular Clocks". Experimental Neurobiology. 20 (1): 18–28. doi:10.5607/en.2011.20.1.18. PMC 3213736 . PMID 22110358.
1 2 Gallego, M; Virshup, DM (2007). "Post-translational modifications regulate the ticking of the circadian clock". Nat Rev Mol Cell Biol. 8 (2): 139–148. doi:10.1038/nrm2106. PMID 17245414. S2CID 27163437.
↑ Toh, KL; Jones, CR; He, Y; Eide, EJ; Hinz, WA; Virshup, DM; Ptacek, LJ; Fu, YH (2001). "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome". Science. 291 (5506): 1040–1043. Bibcode:2001Sci...291.1040T. CiteSeerX 10.1.1.722.460 . doi:10.1126/science.1057499. PMID 11232563. S2CID 1848310.
↑ Price, JL; Blau, J; Rothenfluh, A; Abodeely, M; Kloss, B; Young, MW (1998). "double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation". Cell. 94 (1): 83–95. doi: 10.1016/S0092-8674(00)81224-6 . PMID 9674430.
↑ Tamaru, T; Hirayama, J; Isojima, Y; Nagai, K; Norioka, S; Takamatsu, K; Sassone-Corsi, P (2009). "CK2-alpha phosphorylates BMAL1 to regulate the mammalian clock". Nat Struct Mol Biol. 16 (4): 446–448. doi:10.1038/nsmb.1578. PMC 6501789 . PMID 19330005.
↑ Griffin, EA; Staknis, D; Weitz, CJ (1999). "Light-independent role of CRY1 and CRY2 in the mammalian circadian clock". Science. 286 (5440): 768–71. doi:10.1126/science.286.5440.768. PMID 10531061.
1 2 3 4 Dunlap, JC (1999). "Molecular Bases for Circadian Clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID 9988221.
↑ Akiyama, M; Kouzu, Y; Takahashi, S; Wakamatsu, H; Moriya, T; Maetani, M; Watanabe, S; Tei, H; Sakaki, Y; Shibata, S (1999). "Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms". J. Neurosci. 19 (3): 1115–21. doi:10.1523/jneurosci.19-03-01115.1999. PMC 6782139 . PMID 9920673.
↑ Albrecht, U; Zheng, B; Larkin, D; Sun, ZS; Lee, CC (2001). "MPer1 and mper2 are essential for normal resetting of the circadian clock". J. Biol. Rhythms. 16 (2): 100–4. doi: 10.1177/074873001129001791 . PMID 11302552. S2CID 9067400.
1 2 Hung, HC; Maurer, C; Zorn, D; Chang, WL; Weber, F (2009). "Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein". The Journal of Biological Chemistry. 284 (35): 23734–42. doi: 10.1074/jbc.M109.025064 . PMC 2749147 . PMID 19564332.
↑ Yu, W; Zheng, H; Houl, JH; Dauwalder, B; Hardin, PE (2006). "PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription". Genes Dev. 20 (6): 723–33. doi:10.1101/gad.1404406. PMC 1434787 . PMID 16543224.
↑ Ishida, N; Kaneko, M; Allada, R (1999). "Biological clocks". Proc. Natl. Acad. Sci. U.S.A. 96 (16): 8819–20. Bibcode:1999PNAS...96.8819I. doi: 10.1073/pnas.96.16.8819 . PMC 33693 . PMID 10430850.
↑ Nakajima, M; et al. (2005). "Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro". Science. 308 (5720): 414–5. Bibcode:2005Sci...308..414N. doi:10.1126/science.1108451. PMID 15831759. S2CID 24833877.

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[tuttle-1] Tuttle, LM; Salis, H; Tomshine, J; Kaznessis, YN (2005). "Model-Driven Designs of an Oscillating Gene Network". Biophys. J. 89 (6): 3873–83. Bibcode:2005BpJ....89.3873T. doi:10.1529/biophysj.105.064204. PMC 1366954 . PMID 16183880.

[2] Moreno-Risueno, Miguel; Benfey, Phillip N. (2011). "Time-based patterning in development: the role of oscillating gene expression" (PDF). Landes Bioscience. 2 (3): 124–129. doi:10.4161/trns.2.3.15637. PMC 3149689 . PMID 21826283.

[moore-3] 1 2 Moore, Martin C, Frank M Sulzman, and Charles A Fuller. The Clocks that Time Us: Physiology of the Circadian Timing System. Harvard University Press.

[buhr-4] Buhr, ED; Takahashi, JS (2013). "Molecular Components of the Mammalian Circadian Clock". Acta Oto-Laryngologica. Handbook of Experimental Pharmacology. 109 (5–6): 406–15. doi:10.3109/00016489009125162. PMID 2360447.

[Bretzl-5] 1 2 Von Dr. Hugo Bretzl.'Botanische Forschungen des Alexanderzuges.' Leipzig: Teubner. 1903

[6] Beling, Ingeborg (1929). "Über das Zeitgedächtnis der Bienen". Zeitschrift für Vergleichende Physiologie. 9 (2): 259–338. doi:10.1007/BF00340159. S2CID 39544233.

[Konopka-7] Konopka, RJ; Benzer, Seymour (1971). "Clock Mutants of Drosophila melanogaster". Proceedings of the National Academy of Sciences. 68 (9): 2112–2116. Bibcode:1971PNAS...68.2112K. doi: 10.1073/pnas.68.9.2112 . PMC 389363 . PMID 5002428.

[Hardin-8] 1 2 Hardin, P.E.; Hall, J.C.; Rosbash, M. (1990). "Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels". Nature. 343 (6258): 536–40. Bibcode:1990Natur.343..536H. doi:10.1038/343536a0. PMID 2105471. S2CID 4311836.

[9] Thompson CL, Sancar A (2004). "Cryptochrome: Discovery of a Circadian Photopigment". In Lenci F, Horspool WM. CRC handbook of organic photochemistry and photobiology. Boca Raton: CRC Press. pp. 1381–89. ISBN 0-8493-1348-1.

[10] King, DP; Zhao, Y; Sangoram, AM; Wilsbacher, LD; Tanaka, M; Antoch, MP; Steeves, TD; Vitaterna, MH; Kornhauser, JM; Lowrey, PL; Turek, FW; Takahashi, JS (1997). "Positional Cloning of the Mouse Circadian Clock Gene". Cell. 89 (4): 641–653. doi:10.1016/S0092-8674(00)80245-7. PMC 3815553 . PMID 9160755.

[reppert-11] 1 2 Reppert, Steven M.; Weaver, David R. (2002). "Coordination of circadian timing in mammals". Nature. 418 (6901): 935–941. Bibcode:2002Natur.418..935R. doi:10.1038/nature00965. PMID 12198538. S2CID 4430366.

[Kwon-12] 1 2 3 4 5 6 7 Kwon, I.; Choe, HK; Son, GH; Kyungjin, K (2011). "Mammalian Molecular Clocks". Experimental Neurobiology. 20 (1): 18–28. doi:10.5607/en.2011.20.1.18. PMC 3213736 . PMID 22110358.

[gallego-13] 1 2 Gallego, M; Virshup, DM (2007). "Post-translational modifications regulate the ticking of the circadian clock". Nat Rev Mol Cell Biol. 8 (2): 139–148. doi:10.1038/nrm2106. PMID 17245414. S2CID 27163437.

[Toh-14] Toh, KL; Jones, CR; He, Y; Eide, EJ; Hinz, WA; Virshup, DM; Ptacek, LJ; Fu, YH (2001). "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome". Science. 291 (5506): 1040–1043. Bibcode:2001Sci...291.1040T. CiteSeerX 10.1.1.722.460 . doi:10.1126/science.1057499. PMID 11232563. S2CID 1848310.

[price-15] Price, JL; Blau, J; Rothenfluh, A; Abodeely, M; Kloss, B; Young, MW (1998). "double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation". Cell. 94 (1): 83–95. doi: 10.1016/S0092-8674(00)81224-6 . PMID 9674430.

[tamaru-16] Tamaru, T; Hirayama, J; Isojima, Y; Nagai, K; Norioka, S; Takamatsu, K; Sassone-Corsi, P (2009). "CK2-alpha phosphorylates BMAL1 to regulate the mammalian clock". Nat Struct Mol Biol. 16 (4): 446–448. doi:10.1038/nsmb.1578. PMC 6501789 . PMID 19330005.

[17] Griffin, EA; Staknis, D; Weitz, CJ (1999). "Light-independent role of CRY1 and CRY2 in the mammalian circadian clock". Science. 286 (5440): 768–71. doi:10.1126/science.286.5440.768. PMID 10531061.

[Dunlap-18] 1 2 3 4 Dunlap, JC (1999). "Molecular Bases for Circadian Clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID 9988221.

[19] Akiyama, M; Kouzu, Y; Takahashi, S; Wakamatsu, H; Moriya, T; Maetani, M; Watanabe, S; Tei, H; Sakaki, Y; Shibata, S (1999). "Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms". J. Neurosci. 19 (3): 1115–21. doi:10.1523/jneurosci.19-03-01115.1999. PMC 6782139 . PMID 9920673.

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