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HGNC Approved Gene Symbol: PER1
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:8,140,472-8,152,404 (from NCBI)
PER1 is a master regulator of circadian rhythm and functions in the nucleus to repress expression of the central circadian clock genes (e.g., CLOCK; 601851). The periodicity of PER1 abundance, nuclear translocation, and transcriptional repression is regulated by PER1 phosphorylation, ubiquitination, and proteasomal degradation (summary by Chiu et al. (2011)).
Circadian rhythm is present in all eukaryotic and some prokaryotic life forms. Mammalian circadian regulators must share several common characteristics: they must be expressed in the suprachiasmatic nucleus (SCN); their expression should oscillate with a 24-hour rhythm; circadian expression should persist in the absence of environmental stimuli; and changes in the oscillation of environmental stimuli, such as light, should reset (entrain) the rhythm of expression. Sun et al. (1997) cloned a human gene, termed RIGUI after an ancient Chinese sundial, encoding a protein with basic helix-loop-helix (bHLH) and Per-ARNT-Sim (PAS) domains that is 44% homologous to that of the Drosophila 'Period' gene (Per). By differential splicing, the RIGUI gene gives rise to 3 transcripts of 4.7, 3.0, and 6.6 kb. The RIGUI-4.7 sequence can be translated into a protein of 1,301 amino acids. The open reading frame of RIGUI-6.6 is 875 amino acids long, the first 821 of which are identical to those of RIGUI-4.7. The 798-amino acid open reading frame of RIGUI-3.0 diverges from that of RIGUI-4.7 at amino acid 758. Greatest homology was with the Drosophila Per protein. Sun et al. (1997) reported lesser homology with the mammalian aryl hydrocarbon receptor nuclear translocator (ARNT; 126110) and mouse 'Single minded' (Sim1; see 600892) protein. All 3 genes contain the PAS domain, which is about 260 amino acids long and contains 2 direct repeats of 51 amino acids each. D. melanogaster Per and RIGUI have areas of homology outside the PAS domain that were not observed in comparisons of RIGUI with ARNT, SIM, AHR (600253), NPAS1 (603346), NPAS2 (603347), or CLOCK (601851). From their sequence analysis, Sun et al. (1997) proposed that RIGUI is a human ortholog of Drosophila Per.
By screening a mouse brain cDNA library with human RIGUI-4.7 as probe, Sun et al. (1997) cloned a mouse rigui cDNA. The mouse and human RIGUI protein sequences are 92% identical overall and share 98% identity in the bHLH and PAS domains.
Both human PER1 and mouse Per1 consist of 23 exons spanning approximately 16 kb, and their structures show strong similarity to each other (Hida et al., 2000). For example, 6 highly conserved regions were identified in the 5-prime upstream sequences. These conserved segments exhibited 77 to 88% identity and possessed several potential regulatory elements, including 5 E-boxes (the binding site of the CLOCK-BMAL1 complex) and 4 CAMP response elements (CREs).
Taruscio et al. (2000) also determined that the human PER1 gene contains 23 exons and spans about 15 kb. Sequence alignment indicated that translation is initiated in exon 2. A promoter core was identified, as well as a second regulatory region in intron 1 that appears to exert a negative role in transcriptional control. Several putative splice variants were also identified.
By fluorescence in situ hybridization, Sun et al. (1997) mapped the human PER1 gene to chromosome 17p12.
Sun et al. (1997) found that in mouse retina, the expression of rigui oscillated over a 24-hour period, with highest expression at onset of dark in a 12-hour light/dark cycle, i.e., expression rose during the light period and fell during the dark period. RNA abundance of rigui changed 2.9-fold between highest and lowest levels in mouse retina. Sun et al. (1997) detected oscillation of rigui expression in the SCN, pars tuberalis, and Purkinje neurons of the cerebellum. In the SCN, rigui expression was highest after 6 hours of light in the 12-hour light/dark cycle. Circadian expression of rigui in the SCN persisted under free-running conditions of continual darkness. Shifting the light/dark cycle by 6 hours shifted the rigui expression pattern in the SCN, demonstrating that rigui expression can be entrained. Sun et al. (1997) noted striking diurnal variations of rigui expression; the time of maximal expression differed in the SCN, retina, Purkinje neurons, and pars tuberalis.
The pars tuberalis releases luteinizing hormone, which is negatively regulated by circulating melatonin. The majority of inbred mouse strains, including C57BL/6, have a genetic defect in pineal melatonin biosynthesis and do not produce melatonin (exceptions are C3H/H and CBA). Due to historical backcrosses, the 129/SvEvBrd strain has C3H/H alleles and is likely to generate melatonin. Sun et al. (1997) observed rigui expression in the pars tuberalis of 129/SvEvBrd mice, but not in those of C57BL/6 mice. Sun et al. (1997) suggested that the difference in rigui expression in the pars tuberalis may reflect the difference in melatonin production, implicating melatonin as a regulator of rigui expression in this area of the brain. Several other regions of the brain also expressed rigui, but no changes in expression could be detected in these structures.
Shigeyoshi et al. (1997) examined the effects of light on rigui, designated mouse Per1 by them, which exhibits robust rhythmic expression in the SCN. They found that Per1 is rapidly induced by short duration exposure to light at levels sufficient to reset the clock. Dose-response curves revealed that Per1 induction shows both reciprocity and a strong correlation with phase shifting of the overt rhythm. Thus, in both the phasing of dark expression and the response to light, Per1 is most similar to the Neurospora clock gene frq. Within the SCN, there appears to be localization of the induction phenomenon, consistent with the localization of both light-sensitive and light-insensitive oscillators in this circadian center.
Tei et al. (1997) identified human and mouse genes encoding PAS-domain-containing polypeptides that are highly homologous to the Period protein of Drosophila. They also reported that the mouse Per homolog shows autonomous circadian oscillation in its expression in the SCN, the primary circadian pacemaker in the mammalian brain. Tei et al. (1997) considered it likely that the Per homologs dimerize with other PAS-containing molecules, such as the mammalian Clock gene, through PAS-PAS interaction in the circadian clock system.
Albrecht et al. (1997) reported the isolation of a second murine gene, Per2 (603426), that is homologous to the Drosophila Per gene and has all the properties expected of a circadian clock gene. The overall homology between mouse Per2 and Drosophila Per proteins is 53%, whereas that between mouse Per1 and Drosophila Per proteins is 44%. Expression of Per1 and Per2 is overlapping but asynchronous by 4 hours. Unlike Drosophila Per and mouse Per2, Per1 is expressed rapidly after exposure to light at Circadian Time 22.
Gekakis et al. (1998) used a yeast 2-hybrid screen to find proteins that interact with the Clock protein. The mouse Bmal1 (602550) protein was isolated and found to dimerize with Clock. Bmal1 is found in the suprachiasmatic nucleus and the retina, along with Clock and Per1. The Clock-Bmal1 heterodimers are able to bind DNA and activate transcription from an E-box element (CACGTG), a type of transcription factor-binding site, found adjacent to mouse Per1 and to the Drosophila Per gene. Mutant Clock from the dominant-negative Clock allele forms heterodimers with Bmal1 that bind DNA but fail to activate transcription. The authors concluded that Clock-Bmal1 heterodimers appear to drive the positive component of Per transcriptional oscillations.
Darlington et al. (1998) showed that the Drosophila Clock gene heterodimerizes with the Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the Per promoter and through an 18-bp element encompassing an E-box sequence in the Timeless (TIM; 603887) promoter to activate Per and Tim transcription. Period and Timeless proteins blocked Clock's ability to activate Tim and Per promoters via the E-box. The authors therefore concluded that Clock drives expression of Period and Timeless, which in turn inhibit Clock's activity and close the circadian loop.
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 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 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.
Storch et al. (2002) reported a comparative analysis of circadian gene expression in vivo in mouse liver and heart using oligonucleotide arrays representing 12,488 genes. Peripheral circadian gene regulation was present in 8 to 10% of genes expressed in each tissue, for the distribution of circadian phases in the 2 tissues was markedly different and very few genes showed circadian regulation in both tissues. This specificity of circadian regulation could not be accounted for by tissue-specific gene expression. Despite the divergence, the clock-regulated genes in liver and heart participated in overlapping, extremely diverse processes. A core set of 37 genes with similar circadian regulation in both tissues include candidates for new clock genes and output genes, and it contains genes responsive to circulating factors with circadian or diurnal rhythms.
Casein kinase I-epsilon (CSNK1E; 600863) has a prominent role in regulating the phosphorylation and abundance of Per proteins in animals. Using a Drosophila cell culture system, Ko et al. (2002) demonstrated that doubletime, the Drosophila homolog of CKI-epsilon, promotes the progressive phosphorylation of Per, leading to the rapid degradation of hyperphosphorylated isoforms by the ubiquitin-proteasome pathway. Slimb (BTRC; 603482), an F-box/WD40-repeat protein functioning in the ubiquitin-proteasome pathway, interacts preferentially with phosphorylated Per and stimulates its degradation. Overexpression of slimb or expression in clock cells of a dominant-negative version of slimb disrupts normal rhythmic activity in flies. Ko et al. (2002) concluded that hyperphosphorylated Per is targeted to the proteasome by interactions with Slimb.
Using Drosophila cells and various Per mutants, Chiu et al. (2011) found that Per was progressively phosphorylated by doubletime and the proline-directed serine kinase Nemo (IKBKG; 300248). Per phosphorylation began at a specific cluster of serines at the beginning of the circadian cycle, with additional phosphorylation of Per by doubletime at more distant sites as the cycle progressed. Per phosphorylation increasingly unfolded the protein. Chiu et al. (2011) hypothesized that phosphorylation-dependent Per unfolding makes the protein more susceptible to degradation and releases clock genes from Per-dependent repression.
Von Gall et al. (2002) demonstrated that cycling expression of the clock gene Per1 in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2B receptor (600446), which occurs through the nocturnal activation of melatonin mt1 receptors (600665). Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Per1 and evokes an increase in the release of pituitary prolactin. Von Gall et al. (2002) concluded that their observations expose a mechanism by which 2 convergent signals interact within a temporal dimension to establish high-amplitude, precise, and robust cycles of gene expression.
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 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.
Grima et al. (2004) used targeted expression of Per to restore the clock function of specific subsets of lateral neurons in arrhythmic Per-0 mutant flies. Per expression restricted to the ventral lateral neurons only restored the morning activity, whereas expression of Per in both the ventral lateral neurons and the dorsal lateral neurons also restored the evening activity. Grima et al. (2004) showed that the ventral lateral neurons alone can generate 24 hour activity rhythms in constant darkness, indicating that the morning oscillator is sufficient to drive the circadian system. They concluded that their results provided the first neuronal basis for 'morning' and 'evening' oscillators in the Drosophila brain.
Using experience-dependent courtship behavior in male Drosophila flies as a measure for long-term memory, Sakai et al. (2004) demonstrated that Per mutants are defective in long-term memory formation. The defect was rescued by induction of a wildtype Per transgene in a Per-null mutant, and overexpression of Per enhanced long-term memory formation in the wildtype background. Mutations in other clock genes did not affect long-term memory formation. Sakai et al. (2004) concluded that, independent of the circadian core oscillator, Per plays a key role in long-term memory formation.
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, Nr1d2 (602304), Per2 (603426), 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.
Brown et al. (2005) identified 2 PER1-associated factors, NONO (300084), and WDR5 (609012), that modulate PER activity. The reduction of NONO expression by RNA interference (RNAi) attenuated circadian rhythms in mammalian cells, and fruit flies carrying a hypomorphic allele were nearly arrhythmic. WDR5, a subunit of histone methyltransferase complexes, augmented PER-mediated transcriptional repression, and its reduction by RNAi diminished circadian histone methylation at the promoter of a clock gene.
By fluorescence resonance energy transfer measurements using a single-cell imaging assay with fluorescent forms of PER and TIM (603887), Meyer et al. (2006) showed that these proteins bind rapidly and persist in the cytoplasm while gradually accumulating in discrete foci. After approximately 6 hours, complexes abruptly dissociated, as PER and TIM independently moved to the nucleus in a narrow time frame. The per(l) mutation, which produces a delayed nuclear translocation phenotype in pacemaker cells of the Drosophila brain (Curtin et al., 1995), delayed nuclear accumulation in vivo and in a cultured cell system, but without affecting rates of PER/TIM assembly or dissociation. Meyer et al. (2006) concluded that their finding points to a previously unrecognized form of temporal regulation that underlies the periodicity of the circadian clock.
Gery et al. (2006) found that overexpression of PER1 in human cancer cell lines led to significant growth reduction and sensitized cells to DNA damage-induced apoptosis. In contrast, inhibition of PER1 reduced DNA damage-induced apoptosis. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, PER1 interacted with checkpoint proteins ATM (607585) and CHK2 (CHEK2; 604373). PER1 expression was significantly reduced in lung and breast tumor tissue compared with matched normal tissue.
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.
Belle et al. (2009) found that during the day, neurons containing Per1 sustain an electrically excited state and do not fire, whereas non-Per1 neurons show the previously reported daily variation in firing activity. Using a combined experimental and theoretical approach, Belle et al. (2009) explained how ionic currents lead to the unusual electrophysiologic behaviors of Per1 cells, which unlike other mammalian brain cells can survive and function at depolarized states.
Cao et al. (2009) found rhythmic expression of the Per1 and androgen receptor (AR; 313700) genes in mouse prostate cells, but lack of rhythmic expression of PER1 in human prostate cancer (176807) cells. An expression database showed significant downregulation of PER1 in prostate cancer cells compared to normal prostate tissue. In vitro cellular studies in HEK293 cells and prostate cancer cells demonstrated that PER1 associated with the AR and inhibited AR transcriptional activity, and that activation of AR stimulated transcription of PER1 in a feedback loop. Forced expression of PER1 in 3 different prostate cancer cell lines inhibited AR transcriptional activity, including testosterone stimulation of PSA. The findings suggested that PER1 acts as a negative regulator of AR in prostate cancer cells. The data also supported the hypothesis that disruption of circadian function may contribute to prostate tumorigenesis.
Duong et al. (2011) analyzed protein constituents of PER complexes purified from mouse tissues and identified PSF (605199). Within the complex, PSF functions to recruit SIN3A (607776), a scaffold for assembly transcriptional inhibitory complexes; the PER complex thereby rhythmically delivers histone deacetylases to the PER1 promoter, which repress PER1 transcription. Duong et al. (2011) concluded that their findings provided a function for the PER complex and a molecular mechanism for circadian clock negative feedback.
In mammals, PERIOD (PER1 and PER2; 603426) 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.
Koike et al. (2012) interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and found a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II recruitment, RNA expression, and chromatin states. They found that the circadian transcriptional cycle of the clock consists of 3 distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of mRNA cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. Koike et al. (2012) also found that circadian modulation of RNA polymerase II recruitment and chromatin remodeling occurs on a genomewide scale far greater than that seen previously by gene expression profiling.
Lim and Allada (2013) found that ataxin-2 (ATX2; 601517) is a translational activator of the rate-limiting clock component Per in Drosophila. Atx2 specifically interacted with 'Twenty-four' (Tyf), an activator of Per translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant Atx2 protein that does not associate with polyadenylate-binding protein (PABP; 604679) suppressed behavioral rhythms and decreased abundance of Per. Although Atx2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered Tyf and disrupted the association between Tyf and Pabp. Thus, Lim and Allada (2013) concluded that ATX2 coordinates an active translation complex important for PER expression and circadian rhythms in Drosophila.
Zhang et al. (2013) independently found that the Drosophila homolog of ATX2 was required for circadian locomotor behavior. Atx2 was necessary for Per accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. Atx2 was required for the function of Tyf, a crucial activator of Per translation. Atx2 formed a complex with Tyf and promoted its interaction with Pabp. Zhang et al. (2013) concluded that their work uncovered a role for ATX2 in circadian timing and revealed that this protein functions as an activator of PER translation in circadian neurons.
Penas et al. (2003) cloned a novel cryptic translocation, t(12;17)(p13;p12-p13), occurring in a patient with acute myeloid leukemia evolving from a chronic myelomonocytic leukemia. They identified a fusion transcript between exon 1 of the ETV6 gene (600618) and the antisense strand of PER1. The PER1/ETV6 fusion transcript did not produce a fusion protein, and no other fusion transcripts could be detected. Penas et al. (2003) hypothesized that in the absence of a fusion protein, the inactivation of PER1 or deregulation of a gene in the neighborhood of PER1 may contribute to the pathogenesis of leukemia with this translocation.
Lim et al. (2012) found a significant association between timing of daily activity rhythms in humans and an A-to-G transition (rs7221412) located 2.8 kb downstream of the PER1 gene. Homozygosity for the G allele was associated with a 67-minute delay in acrophase (peak) activity compared to homozygosity for the A allele. A combined analysis of 2 data sets totaling 575 individuals yielded a p value of 2.1 x 10(-7) for the association. The SNP was within a 14-kb haplotype that overlapped with the 3-prime end of the PER1 gene. Analysis of a third cohort of 687 deceased individuals showed an association between the genotype and time of death: under the recessive model, those with the GG genotype had a mean time of death nearly 7 hours later than those with the AA or AG genotype (p = 0.015). PER1 expression levels in postmortem cerebral cortex tissue from another cohort of 193 individuals suggested that the rs7221412 GG genotype was associated with decreased PER1 expression in samples from patients who died during the day compared to those who died during the night. A similar decrease in PER1 expression was also seen in peripheral blood cells from yet another cohort of 297 individuals with the GG genotype who had died during the day. Lim et al. (2012) suggested that polymorphic variation in the PER1 gene may affect gene expression and contribute to multiple aspects of circadian rhythm behavior in humans.
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 (SCN) 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.
To investigate the organization of a mammalian circadian system, Yamazaki et al. (2000) constructed a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Per1 promoter. Light emission from cultured SCN of these rats was invariably and robustly rhythmic and persisted for up to 32 days in vitro. Liver, lung, and skeletal muscle also expressed circadian rhythms, which damped after 2 to 7 cycles in vitro. In response to advances and delays of the environmental light cycle, the circadian rhythm of light emission from the SCN shifted more rapidly than did the rhythm of locomotor behavior or the rhythms in peripheral tissues. Yamazaki et al. (2000) hypothesized that a self-sustained circadian pacemaker in the SCN entrains circadian oscillators in the periphery to maintain adaptive phase control, which is temporarily lost following large, abrupt shifts in the environmental light cycle.
Stokkan et al. (2001) investigated the effects of cycles of food availability on the rhythms of gene expression in the liver, lung, and SCN, using a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Per1 promoter. Although rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver, shifting its rhythm by 10 hours within 2 days. Stokkan et al. (2001) concluded that feeding cycles can entrain the liver independently of the SCN and the light cycle, and they suggested the need to reexamine the mammalian circadian hierarchy. Stokkan et al. (2001) also concluded that their data raise the possibility that peripheral circadian oscillators like those in the liver may be coupled to the SCN primarily through rhythmic behavior, such as feeding.
Yamaguchi et al. (2001) developed a model system in which they were able to follow the rhythmic expression of the mouse clock gene Per1 in the brain of a living mouse. Their model system enabled real-time gene expression to be monitored in the intact brain under physiologic conditions.
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.
To assess the role of mouse Per genes in circadian clock resetting, Albrecht et al. (2001) generated mice carrying a mutant Per1 gene. Per1 mutants were deficient in phase advance responses to light. The authors 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 Per1 in mice. They observed that homozygous mutant mice had severely disrupted locomotor activity rhythms during extended exposure to constant darkness. Using in situ hybridization and immunocytochemistry, Bae et al. (2001) detected that Per2 (603426) and Cry1 clock protein levels were reduced in the SCN of Per1-deficient mice despite unaltered transcript levels. Bae et al. (2001) hypothesized that Per1 influences clock function at a posttranscriptional level, likely through regulating stability of other circadian regulatory proteins via protein-protein interactions. Per1/Per2 double-mutant mice were immediately arrhythmic, displaying a phenotype more consistently severe than either single gene knockout. These findings indicated that Per1 plays an essential role in the maintenance of circadian rhythmicity and influences rhythmicity, primarily through interaction with other clock proteins. Bae et al. (2001) concluded that despite partial compensation between Per1 and Per2, each of the 3 Per genes has a distinct function in the SCN circadian clockwork.
Pando et al. (2002) studied the rhythmic behavior of mouse embryo fibroblasts (MEFs) surgically implanted in mice with different circadian rhythm deficiencies. MEFs from Per1 -/- mice had a much shorter period in culture than did tissues in the intact animal. When implanted back into mice, however, the Per1 -/- MEFs took on the rhythmic characteristics of the host. A functioning clock was found to be required for oscillations in the target tissues, as arrhythmic clock c/c MEFs remained arrhythmic in implants. These results demonstrated that SCN hierarchical dominance can compensate for severe intrinsic genetic defects in peripheral clocks, but cannot induce rhythmicity in clock-defective tissues.
Cheng et al. (2009) functionally characterized 2 mouse transgenic fluorescent clock reporters, Per1-Venus and Per2-DsRED. Imaging of the 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.
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