The PER3 gene encodes the period circadian protein homolog 3 protein in humans. [5] PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans. [6]
The PER3 gene encodes the period circadian protein homolog 3 protein in humans. [5] PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans. [6]
The Per3 gene was independently cloned by two research groups (Kobe University School of Medicine and Harvard Medical School) who both published their discovery in June 1998. [7] [8] The mammalian Per3 was discovered by searching for homologous cDNA sequences to Per2. The amino acid sequence of the mouse PERIOD3 protein (mPER3) is between 37-56% similar to the other two PER proteins. [8] [7]
This gene is a member of the Period family of genes. It is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of gene expression in the SCN. [9] PER1 and PER2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the SCN, but little data is shown on the concrete function for PER3. PER3 was found to be important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3 double knockout (-/-) mice. [10] PER3 may have a stabilizing effect on PER1 and PER2, and this stabilizing effect may be reduced in the PER3-P415A/H417R polymorphism. [11]
The RNA levels of mPer3 oscillate with a circadian rhythm in both the SCN and in the eyes, as well as in peripheral tissues, including the liver, skeletal muscle, and testis. [8] Unlike Per1 and Per2, of which the mRNA is induced in response to light, Per3 mRNA in the SCN does not respond to light. This suggests that Per3 may be regulated differently than either Per1 or Per2. [8]
The mPER3 protein contains a PAS domain, similar to mPER1 and mPER2. Likely, mPER3 binds to other proteins using this domain. [8] However, while PER1/2 have been shown to be important in the transcription-translation feedback loop involved in the intracellular circadian clock, the influence of PER3 in this loop has not yet been fully elucidated, given that mPER3 does not appear to be functionally redundant to mPER1 and mPER2. [12] mPer3 may not be a member of the core clock loop at all. [12]
While the Per3 gene is a paralog to the PER1 and PER2 genes, studies in animals generally show that it does not contribute significantly to circadian rhythms. Functional Per3-/- animals experience only small changes in free-running period, [12] and do not respond significantly differently to light pulses. [13] Per1-/- and Per2-/- animals experience a significant change in free-running period; however, knocking out Per3 in addition to either Per1 or Per2 has little effect on free-running rhythms. [12] Furthermore, Per1-/-Per2-/- mice are completely arrhythmic, indicating that these two genes have much more importance to the biological clock than Per3. [12]
Per3 knockout mice experience a slightly shortened period of locomotor activity (by 0.5 hr [13] ) and are less sensitive to light, in that they entrain more slowly to changes in the light-dark cycle. PER3 may be involved in the suppression of behavioral activity in response to light, although mPer3 expression is not necessary for circadian rhythms. [14] [15]
The PER3 “length” polymorphism in the 54-bp repeat sequence in exon 18 (GenBank accession no. AB047686) is a structural polymorphism due to an insertion or deletion of 18 amino acids in a region encoding a putative phosphorylation domain. The polymorphism has been associated with diurnal preference and delayed sleep phase syndrome. A longer allele polymorphism is associated with “morningness” and the short allele with “eveningness.” The short allele is also associated with delayed sleep phase syndrome. [6] The length polymorphism has also been shown to inhibit adipogenesis and Per3 knockout mice were shown to have increased adipose tissue and decreased muscle tissue compared to wild type. Additionally, the presence of the length polymorphism has also been shown to be associated with type 2 diabetes mellitus (T2DM) patients as compared to non-diabetic control patients. [16] The PER3-P415A/H417R polymorphism has been linked to familial advanced sleep phase syndrome in humans, as well as to seasonal affective disorder, though when knocked in to mice, the polymorphism causes a delayed sleep phase. [11]
The following is a list of some orthologs of the PER3 gene in other species: [17]
The human PER3 gene is located on chromosome 1 at the following location: [18]
PER3 has 19 transcripts (splice variants).
The PER3 protein has been identified to have the following features: [19]
The following are some known post transcriptional modifications to the Per3 gene: [19]
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 principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow it 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.
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.
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 (perS), lengthen (perL), 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.
PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.
Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.
Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.
In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. 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. 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.
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Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.
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Ueli Schibler is a Swiss biologist, chronobiologist and a professor at the University of Geneva. His research has contributed significantly to the field of chronobiology and the understanding of circadian clocks in the body. Several of his studies have demonstrated strong evidence for the existence of robust, self-sustaining circadian clocks in the peripheral tissues.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.