Alternative titles; symbols
HGNC Approved Gene Symbol: PER2
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38) : 2:238,244,044-238,300,065 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | ?Advanced sleep phase syndrome, familial, 1 | 604348 | Autosomal dominant | 3 |
Biologic clocks generate circadian rhythms in physiology and behavior. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the site of a master biological clock. The SCN clock is entrained to the 24-hour day by the daily light-dark cycle, with light acting through both direct and indirect retina-to-SCN pathways. By screening human brain cDNAs for those encoding proteins larger than 100 kD, Nagase et al. (1997) identified KIAA0347, a cDNA encoding a predicted 1,246-amino acid protein homologous to the Drosophila clock gene 'period' (per), which encodes a component of the circadian clock. Shearman et al. (1997) isolated cDNAs encoding Per2, the mouse homolog of PER2. They reported that the predicted human PER2 protein shares 44% and 77% sequence identity with PER1 (602260) and mouse Per2, respectively. PER2 contains a PAS (PER ARNT-SIM) protein dimerization domain and 3 putative bipartite nuclear localization domains. Northern blot analysis revealed that PER2 was expressed as a 7-kb mRNA in all tissues examined. An additional 1.8-kb transcript was also detected in some tissues. Shearman et al. (1997) demonstrated that, in mouse, Per1 and Per2 RNA levels exhibit circadian rhythms in the SCN and eyes. Both Per1 and Per2 transcripts in the SCN are increased by light exposure during subjective night but not during subjective day. The authors concluded that there is a family of mammalian per homologs, and that these genes may function as molecular components of a circadian clock mechanism. Albrecht et al. (1997) reported that the overall homology between mouse Per2 and the Drosophila per protein is 53%. They found that expression of mouse Per1 and Per2 is overlapping but asynchronous by 4 hours.
Toh et al. (2001) determined that the PER2 gene contains 23 exons.
Toh et al. (2001) mapped the human PER2 gene to chromosome 2q by physical mapping within a BAC clone and by FISH.
To investigate the biologic role of NPAS2 (603347), Reick et al. (2001) prepared a neuroblastoma cell line capable of conditional induction of the NPAS2:BMAL1 (602550) heterodimer and identified putative target genes by representational difference analysis, DNA microarrays, and Northern blotting. Coinduction of NPAS2 and BMAL1 activated transcription of the endogenous Per1, Per2, and Cry1 (601933) genes, which encode negatively activating components of the circadian regulatory apparatus, and repressed transcription of the endogenous BMAL1 gene. Analysis of the frontal cortex of wildtype mice kept in a 24-hour light-dark cycle revealed that Per1, Per2, and Cry1 mRNA levels were elevated during darkness and reduced during light, whereas BMAL1 mRNA displayed the opposite pattern. In situ hybridization assays of mice kept in constant darkness revealed that Per2 mRNA abundance did not oscillate as a function of circadian cycle in NPAS2-deficient mice. Thus, NPAS2 likely functions as part of a molecular clock operative in the mammalian forebrain.
NPAS2 has a heme-binding motif. Heme controls activity of the BMAL1-NPAS2 transcription complex in vitro by inhibiting DNA binding in response to carbon monoxide. In mice, Kaasik and Lee (2004) demonstrated that heme differentially modulates expression of the period genes Per1 and Per2 in vivo by a mechanism involving Npas2 and Per2. They showed that Per2 positively stimulates activity of the Bmal1-Npas2 transcription complex and, in turn, Npas2 transcriptionally regulates delta-aminolevulinate synthase (ALAS1; 125290). Vitamin B12 and heme compete for binding to Npas2 and Per2, but they have opposite effects on Per2 and Per1 expression in vivo. Kaasik and Lee (2004) demonstrated that the circadian clock and heme biosynthesis are reciprocally regulated.
Etchegaray et al. (2003) demonstrated that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone (see 602810) acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1, Per2, and Cry1 genes exhibited circadian rhythms in H3 acetylation and RNA polymerase II (see 180660) binding that were synchronous with the corresponding steady-state mRNA rhythms. The histone acetyltransferase p300 (602700) precipitated with Clock (601851) in vivo in a time-dependent manner. Moreover, the Cry proteins inhibited a p300-induced increase in Clock/Bmal1-mediated transcription. Etchegaray et al. (2003) concluded that the delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, was due to the coordinated activities of Rev-Erb-alpha (602408) and Clock/Bmal1, and defined a novel mechanism for circadian phase control.
Toward a system-level understanding of the transcriptional circuitry regulating circadian clocks, Ueda et al. (2005) identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of the transcriptional dynamics. Ueda et al. (2005) found that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the expression of Per1 (602260), Nr1d2 (602304), Per2, Nr1d1 (602408), Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR (600825)-binding elements regulated the transcriptional activity of Arntl (602550), Npas2 (603347), Nfil3 (605327), Clock (601851), Cry1 (601933), and Rorc (602943) through a repressor-precedes-activator pattern as well. DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3 (603427), Nr1d1, Nr1d2, Rora, and Rorb (601972) through a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Ueda et al. (2005) suggested that regulation of E/E-prime boxes is a topologic vulnerability in mammalian circadian clocks, a concept that had been functionally verified using in vitro phenotype assay systems.
Using a reporter gene assay coupled to estrogen response elements (EREs), Gery et al. (2007) showed that PER2 expression reduced the ability of estrogen to activate the ERE in the MCF-7 human breast cancer cell line and in other human estrogen receptor-1 (ESR1; 133430)-positive cancer cell lines. PER2-induced inhibition was associated with ESR1 protein instability. Conversely, silencing of PER2 with small interfering RNA enhanced ERE reporter activity, stabilized the ESR1 protein, and elevated expression of ESR1 target genes. Analysis of the mouse and human PER2 promoters revealed a conserved ERE, and electrophoretic mobility shift analysis demonstrated binding of estrogen-treated MCF-7 cell extracts to this region. Expression of PER2 in MCF-7 cells reduced their growth on plastic and their colony-forming ability in soft agar. Growth inhibition was associated with apoptotic cell death. Gery et al. (2007) concluded that PER2 is involved in a negative-feedback loop that attenuates estrogen stimulation and links the circadian cycle to estrogen receptor signaling.
O'Neill et al. (2008) showed that cAMP signaling constitutes an additional bona fide component of the oscillatory network of the circadian rhythm. They proposed that daily activation of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this way, clock output constitutes an input to subsequent cycles.
Chen et al. (2009) showed that constitutive overexpression of Per2, but not Cry1, severely disrupted circadian rhythms in mouse embryonic fibroblasts and in mouse liver. Constitutive expression of Per2 in brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. Chen et al. (2009) concluded that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and intact organisms. They hypothesized that PER2 directly and rhythmically binds to CLOCK-BMAL1 and bridges CRY to CLOCK-BMAL1 to drive the circadian negative-feedback loop.
In mammals, PERIOD (PER1; 602260 and PER2) and CRYPTOCHROME (CRY1; 601933 and CRY2; 603732) proteins accumulate, form a large nuclear complex (PER complex), and repress their own transcription. Padmanabhan et al. (2012) found that mouse PER complexes included RNA helicases DDX5 (180630) and DHX9 (603115), active RNA polymerase II large subunit (180660), Per and Cry pre-mRNAs, and SETX (608465), a helicase that promotes transcriptional termination. During circadian negative feedback, RNA polymerase II accumulated near termination sites on Per and Cry genes but not on control genes. Recruitment of PER complexes to the elongating polymerase at Per and Cry termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. Circadian clock negative feedback thus includes direct control of transcriptional termination.
Toh et al. (2001) identified a mutation (S662G; 603426.0001) of the PER2 gene in affected members of a large pedigree with familial advanced sleep phase syndrome-1 (FASPS1; 604348). This mutation is within the casein kinase I-epsilon (CSNK1E; 600863)-binding region of PER2 and causes hypophosphorylation of casein kinase I-epsilon in vitro.
Zheng et al. (1999) generated a deletion mutant in the PAS domain of the mouse Per2 gene. Mice homozygous for this deletion displayed a shorter circadian period followed by loss of circadian rhythmicity in constant darkness. The mutation also diminished the oscillating expression of both Per1 (602260) and Per2 in the suprachiasmatic nucleus (SCN), indicating that Per2 may regulate Per1 in vivo.
Okamura et al. (1999) demonstrated that in mice lacking Cry1 (601933) and Cry2 (603732), cyclic expression of Per1 and Per2 is abolished in the suprachiasmatic nucleus and peripheral tissues, and that Per1 and Per2 mRNA levels are constitutively high. The Cry double mutant mice retained the ability to have Per1 and Per2 expression induced by a brief light stimulus known to phase-shift the biologic clock in wildtype animals.
Shearman et al. (2000) demonstrated that in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock (601851) mutant mice, homozygous Per2 mutants, and Cry-deficient mice revealed substantially altered Bmal1 (602550) rhythms, consistent with a dominant role of Per2 in the positive regulation of the Bmal1 loop. In vitro analysis of Cry inhibition of Clock:Bmal1-mediated transcription shows that the inhibition is through direct protein-protein interactions, independent of the Per1 and Tim (603887) proteins. Per2 is a positive regulator of the Bmal1 loop, and Cry1 and Cry2 are the negative regulators of the Period and Cryptochrome cycles.
Zheng et al. (2001) generated mice with a null mutation in the Per1 gene using embryonic stem cell technology. Homozygous Per1 mutants displayed a shorter circadian period with reduced precision and stability. Mice deficient in both Per1 and Per2 did not express circadian rhythms. The authors showed that while Per2 regulates clock gene expression at the transcriptional level, Per1 is dispensable for the rhythmic RNA expression of Per1 and Per2 and may instead regulate Per2 at a posttranscriptional level. Studies of clock-controlled genes revealed a complex pattern of regulation by Per1 and Per2, suggesting independent controls by the 2 proteins over some output pathways. Genes encoding key enzymes in heme biosynthesis were found to be under circadian control and are regulated by Per1 and Per2. Together, these studies showed that Per1 and Per2 have distinct and complementary roles in the mouse clock mechanism.
Fu et al. (2002) reported that mice deficient in the Per2 gene were prone to cancer. After gamma radiation, these mice showed a marked increase in tumor development and reduced apoptosis in thymocytes. The core circadian genes were induced by radiation in wildtype mice but not in Per2 mutant mice. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as cyclin D1 (168461), cyclin A (123835), Mdm2 (164785), and Gadd45-alpha (126335), was deregulated in Per2 mutant mice. In particular, the transcription of Myc (190080) was found to be controlled directly by circadian regulators and was deregulated in the Per2 mutant mice. The authors concluded that the PER2 gene functions in tumor suppression by regulating DNA damage-responsive pathways.
To assess the role of mouse Per genes in circadian clock resetting, Albrecht et al. (2001) generated mice carrying a mutant Per2 gene. They concluded that the mammalian Per genes are not only light-responsive components of the circadian oscillator but are also involved in resetting of the circadian clock.
Using gene targeting, Bae et al. (2001) disrupted Per2 in mice. The homozygous mutant mice had severely disrupted locomotor activity rhythms during extended exposure to constant darkness. Using in situ hybridization, Bae et al. (2001) detected that clock gene RNA rhythms were blunted in the SCN of Per2 mutant mice and hypothesized that Per2 is a positive regulator of circadian gene expression. Per1/Per2 double-mutant mice were immediately arrhythmic, displaying a phenotype more consistently severe than either single gene knockout. These findings indicated that Per2 positively regulates rhythmic gene expression. Bae et al. (2001) concluded that despite partial compensation between products of Per1 and Per2, each of the 3 Per genes has a distinct function in the SCN circadian clockwork.
In mice with a deletion in the PAS domain of the Per2 protein, Spanagel et al. (2005) observed alterations in the glutamatergic system, with lowered expression of the glutamate transporter Eaat1 (SLC1A3; 600111) leading to reduced uptake of glutamate by astrocytes and increased glutamate levels in the extracellular space of mutant mouse brains. The mutant mice also displayed increased alcohol intake. Administration of acamprosate, a drug used to prevent craving and relapse in alcoholic patients, reduced augmented glutamate levels and normalized alcohol consumption in mutant mice. Spanagel et al. (2005) concluded that glutamate is the link between dysfunction of PER2 and enhanced alcohol intake.
In Wistar rats, Lamont et al. (2005) analyzed expression of Per2 in 3 regions of the limbic forebrain known to be involved in emotional regulation, the central nucleus of the amygdala (CeA), the basolateral amygdala (BLA), and the dentate gyrus (DG). Cells in all 3 regions exhibited daily rhythms in the expression of Per2 that were under the control of the SCN, but the rhythm in the CeA was diametrically opposite to those of the BLA and the DG. Adrenalectomy abolished the Per2 rhythm in the CeA but had no effect on Per2 rhythms in the BLA and the DG. Lamont et al. (2005) concluded that key structures of the limbic forebrain exhibit daily oscillations in PER2 expression that are controlled not only by input from the SCN but also by hormonal and neurochemical changes that normally accompany motivational and emotional states, and that cells in these areas may integrate such inputs to modulate circadian rhythms downstream from the SCN clock.
In female rats, Perrin et al. (2006) found that the daily rhythm of Per2 expression was blunted in the metestrus and diestrus phases of the estrous cycle within 2 nuclei of the limbic forebrain: the oval nucleus of the bed nucleus of the stria terminalis and the central nucleus of the amygdala. Similar changes were not seen in the suprachiasmatic nucleus, dentate gyrus, or basolateral amygdala. Blunting of Per2 rhythm at these phases of the cycle was abolished by ovariectomy and restored by phasic estrogen replacement, suggesting that fluctuations in estrogen levels or their sequelae are necessary to produce these effects. The findings suggested that the phase of the reproductive cycle has a profound effect on the oscillation of clock genes within the brain.
Using mass spectrometry, Vanselow et al. (2006) identified 21 residues in mouse Per2 that were phosphorylated in living cells, including ser659, which corresponds to the ser662 residue of human PER2 that is mutated (see 603426.0001) in FASPS. Expression of FASPS-mutated Per2 in oscillating fibroblasts resulted in a phenocopy of the short period and advanced phase seen in FASPS patients. Vanselow et al. (2006) demonstrated that phosphorylation at ser659 results in nuclear retention and stabilization of Per2, whereas mutation at ser659 leads to an accelerated nuclear clearance of Per2. Mathematical modeling predicted that differential PER phosphorylation events could result in opposite period phenotypes, and studies in oscillating fibroblasts confirmed that interference with specific aspects of Per2 phosphorylation leads to either short or long periods. Vanselow et al. (2006) concluded that this concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster and double-time mutations in Drosophila (see CSNK1E; 600863).
Xu et al. (2007) found that transgenic mice with the human S662G mutation recapitulated the human FASPS phenotype. Functional studies showed that phosphorylation at ser662 plays a critical role in the regulation of PER2 by CSNK1E via a cascade of phosphorylations that requires a priming event at ser662. This phosphorylation resulted in increased PER2 transcription and accumulation of protein in the nucleus. Altering CSNK1E dosage modulated the S662G phenotype but not wildtype PER2. Further studies suggested that phosphorylation of another site on PER2 by CSNK1E targets PER2 for degradation, indicating that CSNK1E regulates the periodicity of PER2.
Cheng et al. (2009) functionally characterized 2 mouse transgenic fluorescent clock reporters, mouse Per1 (602260)-Venus and mouse Per2-DsRED. Imaging of the suprachiasmatic nucleus (SCN) revealed oscillations, as well as light inducibility, in Per1 and Per2 expression. Rhythmic Per1 and Per2 expression was observed in distinct SCN cell populations, suggesting the existence of discrete cellular SCN clocks. Outside of the SCN, Per1 expression was broadly expressed in neuronal and nonneuronal populations. Conversely, Per2 was expressed in glial populations and progenitor cells of the dentate gyrus; limited expression was detected in neurons. Cheng et al. (2009) hypothesized that the central nervous system possesses mechanistically distinct subpopulations of neuronal and nonneuronal cellular clocks.
Using a circadian clock reporter mouse model, Janich et al. (2011) showed that the dormant hair follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 (602550) modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal aging, and a reduction in the development of squamous tumors. Janich et al. (2011) concluded that their results indicated that the circadian clock fine tunes the temporal behavior of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
In a 4-generation pedigree segregating autosomal dominant familial advanced sleep phase syndrome-1 (FASPS1; 604348), Toh et al. (2001) identified a complex banding pattern in exon 17 of the PER2 gene. Sequencing of this exon from affected individuals revealed 4 base changes. Three of the changes, an A-to-G substitution at nucleotide 2078, an A-to-G substitution at nucleotide 2114, and an A-to-G substitution at nucleotide 2117, occurred at wobble positions and were therefore synonymous mutations. One change, however, a 2106A-G transition that resulted in a ser662-to-gly (S662G) substitution, was not identified in 92 control individuals. The S662G change cosegregated with the FASPS phenotype in this family except in a small branch where the marker alleles were unlinked to chromosome 2q. The mutation was found to result in decreased phosphorylation by casein kinase I-epsilon.
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