CLOCK
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Location (UCSC) | Chr 4: 55.43 – 55.55 Mb | Chr 5: 76.36 – 76.45 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
CLOCK (from circadian locomotor output cycles kaput) is a
Research shows that the CLOCK gene plays a major role as an activator of downstream elements in the pathway critical to the generation of circadian rhythms.[5][6]
Discovery
The CLOCK gene was first identified in 1997 by
Function
CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.
A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome (cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry.[12] The heterodimer CLOCK:BMAL1 functions similarly to other transcriptional activator complexes; CLOCK:BMAL1 interacts with the E-box regulatory elements. PER and CRY proteins accumulate and dimerize during subjective night, and translocate into the nucleus to interact with the CLOCK:BMAL1 complex, directly inhibiting their own expression. This research has been conducted and validated through crystallographic analysis.[13]
CLOCK exhibits
Role in other feedback loops
The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzyme
The CLOCK-BMAL dimer acts as a positive limb of a feedback loop. The binding of CLOCK-BMAL to an E-box promoter element activates transcription of clock genes such as per1, 2, and 3 and tim in mice. It has been shown in mice that CLOCK-BMAL also activates the
Evolution
Phylogeny
The first
Variant allele forms
Allelic variations within the Clock1a gene in particular are hypothesized to have effects on seasonal timing according to a 2014 study conducted in a population of cyprinid fishes.[21] Polymorphisms in the gene mainly affect the length of the PolyQ domain region, providing an example of divergent evolution where species sharing an ecological niche will partition resources in seasonally variable environments.[21] The length of the PolyQ domain is associated with changes in transcription level of CLOCK. On average, longer allele lengths were correlated with recently derived species and earlier-spawning species, most likely due to seasonal changes in water temperature.[21] The researchers hypothesize that the length of the domain may serve to compensate for changes in temperature by altering the rate of CLOCK transcription. All other amino acids remained identical across native species, indicating that functional constraint may be another factor influencing CLOCK gene evolution in addition to gene duplication and diversification.[20][21]
Role in mammalian evolution
One 2017 study investigating the role of CLOCK expression in neurons determined its function in regulating transcriptional networks that could provide insight into human brain evolution.
Mutants
Clock mutant organisms can either possess a null mutation or an antimorphic allele at the Clock locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by Clock.[24]
Drosophila
In Drosophila, a mutant form of Clock (Jrk) was identified by Allada, Hall, and Rosbash in 1998. The team used forward genetics to identify non-circadian rhythms in mutant flies. Jrk results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of 24.8 hours, while the other half become arrhythmic. Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects.[25] The similar sequence between Jrk and its mouse homolog suggests common circadian rhythm components were present in both Drosophila and mice ancestors. A recessive allele of Clock leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms.[26]
Mice
The mouse homolog to the Jrk mutant is the ClockΔ19 mutant that possesses a deletion in exon 19 of the Clock gene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate per transcription. In constant darkness, ClockΔ19 mice heterozygous for the Clock mutant allele exhibit lengthened circadian periods, while ClockΔ19/Δ19 mice homozygous for the allele become arrhythmic.[8] In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level.[27]
Clock -/- null mutant mice, in which Clock has been knocked out, display completely normal circadian rhythms. The discovery of a null Clock mutant with a wild-type phenotype directly challenged the widely accepted premise that Clock is necessary for normal circadian function. Furthermore, it suggested that the CLOCK-BMAL1 dimer need not exist to modulate other elements of the circadian pathway.
Observed effects
In humans, a
In mice, Clock has been implicated in
The CLOCK-BMAL dimer has also been shown to activate reverse-erb receptor alpha (
Variations in the epigenetics of the Clock gene may lead to an increased risk of breast cancer.[43] It was found that in women with breast cancer, there was significantly less methylation of the Clock promoter region. It was also noted that this effect was greater in women with estrogen and progesterone receptor-negative tumors.[44]
The CLOCK gene may also be a target for somatic mutations in microsatellite unstable colorectal cancers. In one study, 53% of microsatellite instability colorectal cancer cases contained somatic CLOCK mutations.[45] Nascent research in the expression of circadian genes in adipose tissue suggests that suppression of the CLOCK gene may causally correlate not only with obesity, but also with type 2 diabetes,[46] with quantitative physical responses to circadian food intake as potential inputs to the clock system.[47]
See also
- BMAL1gene
- Cycle gene
- Familial sleep traits
- PDF (gene)
- Period gene
- Pigment dispersing factor (pdf)
- Suprachiasmatic nucleus
- Timeless gene
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000134852 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029238 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 91120424.
- ^ S2CID 14991100.
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- ^ PMID 9779516.
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- S2CID 15224136.
- S2CID 33279857.
- ^ Dodson H. "Women With Variants in "CLOCK" Gene Have Higher Risk of Breast Cancer". Yale Office of Public Affairs and Communications. Archived from the original on 2011-07-24. Retrieved 21 April 2011.
- PMID 25198253.
- PMID 20551151.
- PMID 23801717.
- PMID 24666537.
Further reading
- Wager-Smith K, Kay SA (September 2000). "Circadian rhythm genetics: from flies to mice to humans". Nature Genetics. 26 (1): 23–27. S2CID 6923885.
External links
- Clock+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Dictionary of Circadian Physiology
- Human CLOCK genome location and CLOCK gene details page in the UCSC Genome Browser.