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Daniel Leite Goes Gitai - One of the best experts on this subject based on the ideXlab platform.
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rhythms of core clock genes and spontaneous locomotor activity in post status epilepticus model of mesial temporal lobe epilepsy
Frontiers in Neurology, 2018Co-Authors: Heloisa De Carvalho Matos, Wanessa S Pereira, Tiago Gomes De Andrade, Olagide W Castro, Marcelo Duzzioni, Maheedhar Kodali, Joao P Leite, Ashok K Shetty, Bruna Del Vechio Koike, Daniel Leite Goes GitaiAbstract:The interaction of Mesial Temporal Lobe Epilepsy (mTLE) with the circadian system control is apparent from an oscillatory pattern of limbic seizures, daytime’s effect on seizure onset and the efficacy of antiepileptic drugs. Moreover, seizures per se can interfere with the biological rhythm output, including circadian oscillation of body temperature, locomotor activity, EEG pattern as well as the transcriptome. However, the molecular mechanisms underlying this cross-talk remain unclear. In this study, we systematically evaluated the temporal expression of seven core circadian transcripts (Bmal1, Clock, Cry1, Cry2, Per1, Per2, and PER3) and the spontaneous locomotor activity (SLA) in post-status epilepticus (SE) model of mTLE. Twenty-four hour oscillating spontaneous locomotor activity (SLA) remained intact in post-SE groups although the circadian phase and the amount and intensity of activity were changed in early post-SE and epileptic phases. The acrophase of the SLA rhythm was delayed during epileptogenesis, a fragmented 24h rhythmicity and extended active phase length appeared in the epileptic phase. The temporal expression of circadian transcripts Bmal1, Cry1, Cry2, Per1, Per2, and PER3 was also substantially altered. The oscillatory expression of Bmal1 was maintained in rats imperiled to SE, but with lower amplitude (A= 0.2) and an advanced acrophase in the epileptic phase. The diurnal rhythm of Cry1 and Cry2 was absent in the early post-SE but was recovered in the epileptic phase. Per1 and Per2 rhythmic expression were disrupted in post-SE groups while PER3 presented an arrhythmic profile in the epileptic phase, only. The expression of Clock did not display rhythmic pattern in any condition. These oscillating patterns of core clock genes may contribute to hippocampal 24-hour cycling and, consequently to seizure periodicity. Furthermore, by using a pool of samples collected at 6 different Zeitgeber Times (ZT), we found that all clock transcripts were significantly dysregulated after SE induction, except PER3 and Per2. Collectively, altered SLA rhythm in early post-SE and epileptic phases implies a possible role for seizure as a nonphotic cue, which is likely linked to activation of hippocampal–accumbens pathway. On the other hand, altered temporal expression of the clock genes after SE suggests their involvement in the MTLE.
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rhythms of core clock genes and spontaneous locomotor activity in post status epilepticus model of mesial temporal lobe epilepsy
Frontiers in Neurology, 2018Co-Authors: Heloisa De Carvalho Matos, Bruna Del Vechio Koike, Wanessa S Pereira, Tiago Gomes De Andrade, Olagide W Castro, Marcelo Duzzioni, Maheedhar Kodali, Joao P Leite, Ashok K Shetty, Daniel Leite Goes GitaiAbstract:The interaction of Mesial Temporal Lobe Epilepsy (mTLE) with the circadian system control is apparent from an oscillatory pattern of limbic seizures, daytime's effect on seizure onset and the efficacy of antiepileptic drugs. Moreover, seizures per se can interfere with the biological rhythm output, including circadian oscillation of body temperature, locomotor activity, EEG pattern as well as the transcriptome. However, the molecular mechanisms underlying this cross-talk remain unclear. In this study, we systematically evaluated the temporal expression of seven core circadian transcripts (Bmal1, Clock, Cry1, Cry2, Per1, Per2, and PER3) and the spontaneous locomotor activity (SLA) in post-status epilepticus (SE) model of mTLE. Twenty-four hour oscillating SLA remained intact in post-SE groups although the circadian phase and the amount and intensity of activity were changed in early post-SE and epileptic phases. The acrophase of the SLA rhythm was delayed during epileptogenesis, a fragmented 24 h rhythmicity and extended active phase length appeared in the epileptic phase. The temporal expression of circadian transcripts Bmal1, Cry1, Cry2, Per1, Per2, and PER3 was also substantially altered. The oscillatory expression of Bmal1 was maintained in rats imperiled to SE, but with lower amplitude (A = 0.2) and an advanced acrophase in the epileptic phase. The diurnal rhythm of Cry1 and Cry2 was absent in the early post-SE but was recovered in the epileptic phase. Per1 and Per2 rhythmic expression were disrupted in post-SE groups while PER3 presented an arrhythmic profile in the epileptic phase, only. The expression of Clock did not display rhythmic pattern in any condition. These oscillating patterns of core clock genes may contribute to hippocampal 24 h cycling and, consequently to seizure periodicity. Furthermore, by using a pool of samples collected at 6 different Zeitgeber Times (ZT), we found that all clock transcripts were significantly dysregulated after SE induction, except PER3 and Per2. Collectively, altered SLA rhythm in early post-SE and epileptic phases implies a possible role for seizure as a nonphotic cue, which is likely linked to activation of hippocampal-accumbens pathway. On the other hand, altered temporal expression of the clock genes after SE suggests their involvement in the MTLE.
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diurnal variation has effect on differential gene expression analysis in the hippocampus of the pilocarpine induced model of mesial temporal lobe epilepsy
PLOS ONE, 2015Co-Authors: Evelin Antonieli Da Silva Santos, Thalita Ewellyn Batista Sales Marques, Heloisa De Carvalho Matos, Joao Pereira Leite, Norberto Garciacairasco, Maria Luisa Pacolarson, Daniel Leite Goes GitaiAbstract:The molecular mechanisms underlying epileptogenesis have been widely investigated by differential gene expression approach, especially RT-qPCR methodology. However, controversial findings highlight the occurrence of unpredictable sources of variance in the experimental designs. Here, we investigated if diurnal rhythms of transcript’s levels may impact on differential gene expression analysis in hippocampus of rats with experimental epilepsy. For this, we have selected six core clock genes (Per1, PER3, Bmal1, Clock, Cry1 and Cry2), whose rhythmic expression pattern in hippocampus had been previously reported. Initially, we identified Tubb2a/Rplp1 and Tubb2a/Ppia as suitable normalizers for circadian studies in hippocampus of rats maintained to 12:12 hour light:dark (LD) cycle. Next, we confirmed the temporal profiling of Per1, PER3, Bmal1, Cry1 and Cry2 mRNA levels in the hippocampus of naive rats by both Acrophase and CircWave statistical tests for circadian analysis. Finally, we showed that temporal differences of sampling can change experimental results for Per1, PER3, Bmal1, Cry1 and Cry2, but not for Clock, which was consistently decreased in rats with epilepsy in all comparison to the naive group. In conclusion, our study demonstrates it is mandatory to consider diurnal oscillations, in order to avoid erroneous conclusions in gene expression analysis in hippocampus of rats with epilepsy. Investigators, therefore, should be aware that genes with circadian expression could be out of phase in different animals of experimental and control groups. Moreover, our results indicate that a sub-expression of Clock may be involved in epileptogenicity, although the functional significance of this remains to be investigated.
Heloisa De Carvalho Matos - One of the best experts on this subject based on the ideXlab platform.
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rhythms of core clock genes and spontaneous locomotor activity in post status epilepticus model of mesial temporal lobe epilepsy
Frontiers in Neurology, 2018Co-Authors: Heloisa De Carvalho Matos, Wanessa S Pereira, Tiago Gomes De Andrade, Olagide W Castro, Marcelo Duzzioni, Maheedhar Kodali, Joao P Leite, Ashok K Shetty, Bruna Del Vechio Koike, Daniel Leite Goes GitaiAbstract:The interaction of Mesial Temporal Lobe Epilepsy (mTLE) with the circadian system control is apparent from an oscillatory pattern of limbic seizures, daytime’s effect on seizure onset and the efficacy of antiepileptic drugs. Moreover, seizures per se can interfere with the biological rhythm output, including circadian oscillation of body temperature, locomotor activity, EEG pattern as well as the transcriptome. However, the molecular mechanisms underlying this cross-talk remain unclear. In this study, we systematically evaluated the temporal expression of seven core circadian transcripts (Bmal1, Clock, Cry1, Cry2, Per1, Per2, and PER3) and the spontaneous locomotor activity (SLA) in post-status epilepticus (SE) model of mTLE. Twenty-four hour oscillating spontaneous locomotor activity (SLA) remained intact in post-SE groups although the circadian phase and the amount and intensity of activity were changed in early post-SE and epileptic phases. The acrophase of the SLA rhythm was delayed during epileptogenesis, a fragmented 24h rhythmicity and extended active phase length appeared in the epileptic phase. The temporal expression of circadian transcripts Bmal1, Cry1, Cry2, Per1, Per2, and PER3 was also substantially altered. The oscillatory expression of Bmal1 was maintained in rats imperiled to SE, but with lower amplitude (A= 0.2) and an advanced acrophase in the epileptic phase. The diurnal rhythm of Cry1 and Cry2 was absent in the early post-SE but was recovered in the epileptic phase. Per1 and Per2 rhythmic expression were disrupted in post-SE groups while PER3 presented an arrhythmic profile in the epileptic phase, only. The expression of Clock did not display rhythmic pattern in any condition. These oscillating patterns of core clock genes may contribute to hippocampal 24-hour cycling and, consequently to seizure periodicity. Furthermore, by using a pool of samples collected at 6 different Zeitgeber Times (ZT), we found that all clock transcripts were significantly dysregulated after SE induction, except PER3 and Per2. Collectively, altered SLA rhythm in early post-SE and epileptic phases implies a possible role for seizure as a nonphotic cue, which is likely linked to activation of hippocampal–accumbens pathway. On the other hand, altered temporal expression of the clock genes after SE suggests their involvement in the MTLE.
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rhythms of core clock genes and spontaneous locomotor activity in post status epilepticus model of mesial temporal lobe epilepsy
Frontiers in Neurology, 2018Co-Authors: Heloisa De Carvalho Matos, Bruna Del Vechio Koike, Wanessa S Pereira, Tiago Gomes De Andrade, Olagide W Castro, Marcelo Duzzioni, Maheedhar Kodali, Joao P Leite, Ashok K Shetty, Daniel Leite Goes GitaiAbstract:The interaction of Mesial Temporal Lobe Epilepsy (mTLE) with the circadian system control is apparent from an oscillatory pattern of limbic seizures, daytime's effect on seizure onset and the efficacy of antiepileptic drugs. Moreover, seizures per se can interfere with the biological rhythm output, including circadian oscillation of body temperature, locomotor activity, EEG pattern as well as the transcriptome. However, the molecular mechanisms underlying this cross-talk remain unclear. In this study, we systematically evaluated the temporal expression of seven core circadian transcripts (Bmal1, Clock, Cry1, Cry2, Per1, Per2, and PER3) and the spontaneous locomotor activity (SLA) in post-status epilepticus (SE) model of mTLE. Twenty-four hour oscillating SLA remained intact in post-SE groups although the circadian phase and the amount and intensity of activity were changed in early post-SE and epileptic phases. The acrophase of the SLA rhythm was delayed during epileptogenesis, a fragmented 24 h rhythmicity and extended active phase length appeared in the epileptic phase. The temporal expression of circadian transcripts Bmal1, Cry1, Cry2, Per1, Per2, and PER3 was also substantially altered. The oscillatory expression of Bmal1 was maintained in rats imperiled to SE, but with lower amplitude (A = 0.2) and an advanced acrophase in the epileptic phase. The diurnal rhythm of Cry1 and Cry2 was absent in the early post-SE but was recovered in the epileptic phase. Per1 and Per2 rhythmic expression were disrupted in post-SE groups while PER3 presented an arrhythmic profile in the epileptic phase, only. The expression of Clock did not display rhythmic pattern in any condition. These oscillating patterns of core clock genes may contribute to hippocampal 24 h cycling and, consequently to seizure periodicity. Furthermore, by using a pool of samples collected at 6 different Zeitgeber Times (ZT), we found that all clock transcripts were significantly dysregulated after SE induction, except PER3 and Per2. Collectively, altered SLA rhythm in early post-SE and epileptic phases implies a possible role for seizure as a nonphotic cue, which is likely linked to activation of hippocampal-accumbens pathway. On the other hand, altered temporal expression of the clock genes after SE suggests their involvement in the MTLE.
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diurnal variation has effect on differential gene expression analysis in the hippocampus of the pilocarpine induced model of mesial temporal lobe epilepsy
PLOS ONE, 2015Co-Authors: Evelin Antonieli Da Silva Santos, Thalita Ewellyn Batista Sales Marques, Heloisa De Carvalho Matos, Joao Pereira Leite, Norberto Garciacairasco, Maria Luisa Pacolarson, Daniel Leite Goes GitaiAbstract:The molecular mechanisms underlying epileptogenesis have been widely investigated by differential gene expression approach, especially RT-qPCR methodology. However, controversial findings highlight the occurrence of unpredictable sources of variance in the experimental designs. Here, we investigated if diurnal rhythms of transcript’s levels may impact on differential gene expression analysis in hippocampus of rats with experimental epilepsy. For this, we have selected six core clock genes (Per1, PER3, Bmal1, Clock, Cry1 and Cry2), whose rhythmic expression pattern in hippocampus had been previously reported. Initially, we identified Tubb2a/Rplp1 and Tubb2a/Ppia as suitable normalizers for circadian studies in hippocampus of rats maintained to 12:12 hour light:dark (LD) cycle. Next, we confirmed the temporal profiling of Per1, PER3, Bmal1, Cry1 and Cry2 mRNA levels in the hippocampus of naive rats by both Acrophase and CircWave statistical tests for circadian analysis. Finally, we showed that temporal differences of sampling can change experimental results for Per1, PER3, Bmal1, Cry1 and Cry2, but not for Clock, which was consistently decreased in rats with epilepsy in all comparison to the naive group. In conclusion, our study demonstrates it is mandatory to consider diurnal oscillations, in order to avoid erroneous conclusions in gene expression analysis in hippocampus of rats with epilepsy. Investigators, therefore, should be aware that genes with circadian expression could be out of phase in different animals of experimental and control groups. Moreover, our results indicate that a sub-expression of Clock may be involved in epileptogenicity, although the functional significance of this remains to be investigated.
Qian Bo-zhang - One of the best experts on this subject based on the ideXlab platform.
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tfeb regulates PER3 expression via glucose dependent effects on clock bmal1
The International Journal of Biochemistry & Cell Biology, 2016Co-Authors: Wenwen Luo, Yunzhi Yang, Chenyao Wang, Qian Bo-zhang, Deyi Zhang, Yi Liu, Zhixue LiuAbstract:It has been reported that metabolites regulate circadian rhythms through direct effects on clock genes. A metabolic network involving PER3 raises the possibility that some metabolic regulators are directly involved in the mammalian clock. Here, we show that the bHLH family transcription factor TFEB regulates PER3 through the CLOCK/BMAL1 complex. In the liver, TFEB expression displays circadian rhythms. A loss of TFEB function disrupts and dampens the expression of PER3 but not the expression of other circadian genes, such as PER1, PER2, CRY1 and CRY2. TFEB physically interacts with CLOCK/BMAL1 through its N-terminal region. In the presence of TFEB, BMAL1/CLOCK-mediated transcription is enhanced. Moreover, the TFEB/CLOCK/BMAL1 complex is regulated by glucose. These results show that TFEB has a role in the mammalian clock mechanism.
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TFEB regulates PER3 expression via glucose-dependent effects on CLOCK/BMAL1.
The International Journal of Biochemistry & Cell Biology, 2016Co-Authors: Shumin Ma, Yunzhi Yang, Chenyao Wang, Deyi Zhang, Qian Bo-zhangAbstract:It has been reported that metabolites regulate circadian rhythms through direct effects on clock genes. A metabolic network involving PER3 raises the possibility that some metabolic regulators are directly involved in the mammalian clock. Here, we show that the bHLH family transcription factor TFEB regulates PER3 through the CLOCK/BMAL1 complex. In the liver, TFEB expression displays circadian rhythms. A loss of TFEB function disrupts and dampens the expression of PER3 but not the expression of other circadian genes, such as PER1, PER2, CRY1 and CRY2. TFEB physically interacts with CLOCK/BMAL1 through its N-terminal region. In the presence of TFEB, BMAL1/CLOCK-mediated transcription is enhanced. Moreover, the TFEB/CLOCK/BMAL1 complex is regulated by glucose. These results show that TFEB has a role in the mammalian clock mechanism.
Rae Silver - One of the best experts on this subject based on the ideXlab platform.
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Differential localization of PER1 and PER2 in the brain master circadian clock.
The European journal of neuroscience, 2016Co-Authors: Malini Riddle, Joseph Lesauter, Erica Mezias, Duncan K. Foley, Rae SilverAbstract:The hypothalamic suprachiasmatic nucleus (SCN), locus of the master circadian clock, bears many neuronal types. At the cellular-molecular level, the clock is comprised of feedback loops involving 'clock' genes including Period1 and Period2, and their protein products, PERIOD1 and PERIOD2 (PER1/2). In the canonical model of circadian oscillation, the PER1/2 proteins oscillate together. While their rhythmic expression in the SCN as a whole has been described, the possibility of regional differences remains unknown. To explore these clock proteins in distinct SCN regions, we assessed their expression through the rostro-caudal extent of the SCN in sagittal sections. We developed an automated method for tracking three fluorophores in digital images of sections triply labeled for PER1, PER2, and gastrin-releasing peptide (used to locate the core). In the SCN as a whole, neurons expressing high levels of PER2 were concentrated in the rostral, rostrodorsal, and caudal portions of the nucleus, and those expressing high levels of PER1 lay in a broad central area. Within these overall patterns, adjacent cells differed in expression levels of the two proteins. The results demonstrate spatially distinct localization of high PER1 vs. PER2 expression, raising the possibility that their distribution is functionally significant in encoding and communicating temporal information. The findings provoke the question of whether there are fundamental differences in PER1/2 levels among SCN neurons and/or whether topographical differences in protein expression are a product of SCN network organization rather than intrinsic differences among neurons.
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A short half-life GFP mouse model for analysis of suprachiasmatic nucleus organization
Brain Research, 2003Co-Authors: Joseph Lesauter, Douglas G. Mcmahon, Sandra J. Kuhlman, Jorge E. Quintero, Lily Yan, Bhavana Vishnubhotla, Rae SilverAbstract:Period1 (Per1) is one of several clock genes driving the oscillatory mechanisms that mediate circadian rhythmicity. Per1 mRNA and protein are highly expressed in the suprachiasmatic nuclei, which contain oscillator cells that drive circadian rhythmicity in physiological and behavioral responses. We examined a transgenic mouse in which degradable green fluorescent protein (GFP) is driven by the mPer1 gene promoter. This mouse expresses precise free-running rhythms and characteristic light induced phase shifts. GFP protein (reporting Per1 mRNA) is expressed rhythmically as measured by either fluorescence or immunocytochemistry. In addition the animals show predicted rhythms of Per1 mRNA, PER1 and PER2 proteins. The localization of GFP overlaps with that of Per1 mRNA, PER1 and PER2 proteins. Together, these results suggest that GFP reports rhythmic Per1 expression. A surprising finding is that, at their peak expression time GFP, Per1 mRNA, PER1 and PER2 proteins are absent or not detectable in a subpopulation of SCN cells located in the core region of the nucleus.
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Research report A half-life GFP mouse model for analysis of suprachiasmatic nucleus organization
2003Co-Authors: Joseph Lesauter, Douglas G. Mcmahon, Sandra J. Kuhlman, Jorge E. Quintero, Lily Yan, Bhavana Vishnubhotla, Rae SilverAbstract:Period1 (Per1 ) is one of several clock genes driving the oscillatory mechanisms that mediate circadian rhythmicity. Per1 mRNA and protein are highly expressed in the suprachiasmatic nuclei, which contain oscillator cells that drive circadian rhythmicity in physiological and behavioral responses. We examined a transgenic mouse in which degradable green fluorescent protein (GFP) is driven by the mPer1 gene promoter. This mouse expresses precise free-running rhythms and characteristic light induced phase shifts. GFP protein (reporting Per1 mRNA) is expressed rhythmically as measured by either fluorescence or immunocytochemistry. In addition the animals show predicted rhythms of Per1 mRNA, PER1 and PER2 proteins. The localization of GFP overlaps with that of Per1 mRNA, PER1 and PER2 proteins. Together, these results suggest that GFP reports rhythmic Per1 expression. A surprising finding is that, at their peak expression time GFP, Per1 mRNA, PER1 and PER2 proteins are absent or not detectable in a subpopulation of SCN cells located in the core region of the nucleus. 2002 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behavior Topic: Biological rhythms
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expression of period genes rhythmic and nonrhythmic compartments of the suprachiasmatic nucleus pacemaker
The Journal of Neuroscience, 2001Co-Authors: Toshiyuki Hamada, Joseph Lesauter, Rae Silver, Judith M VenutiAbstract:The mammalian circadian clock lying in the suprachiasmatic nucleus (SCN) controls daily rhythms and synchronizes the organism to its environment. In all organisms studied, circadian timekeeping is cell-autonomous, and rhythmicity is thought to be generated by a feedback loop involving clock proteins that inhibit transcription of their own genes. In the present study, we examined how these cellular properties are organized within the SCN tissue to produce rhythmicity and photic entrainment. The results show that the SCN has two compartments regulating Period genes Per1 , Per2 , and PER3 mRNA expression differentially. One compartment shows endogenous rhythmicity in Per1 , Per2 , and PER3 mRNA expression. The other compartment does not have rhythmic mRNA expression but has gated light-induced Per1 and Per2 and high levels of endogenous nonrhythmic PER3 mRNA expression. These results reveal the occurrence of differential regulation of clock genes in two distinct SCN regions and suggest a potential mechanism for producing functional differences in distinct SCN subregions.
Simon Archer - One of the best experts on this subject based on the ideXlab platform.
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Light-dependent behavioral phenotypes in PER3-deficient mice.
Journal of biological rhythms, 2010Co-Authors: Daan R. Van Der Veen, Simon ArcherAbstract:A functional knockout of Period3 in mice (mPER3— /—) results in a mildly altered circadian phenotype, and mPER3 shows a redundant role within the circadian clock. In this study, the authors reevaluated the PER3—/ — behavioral phenotype on a C57Bl/6J background and report altered responses to light. In constant light, free-running activity period was shorter than that of wild-type, whereas in constant darkness, no difference was observed between genotypes. The effect of light was parametric, and the difference in free-running period between genotypes increased under constant light with increasing light intensity. An attenuated response to light in PER3—/— mice was also demonstrated through reduced negative masking in activity in an ultradian protocol and a slower reentrainment to a shifted light-dark cycle when activity falls in the light period of the new light-dark cycle. Behavioral phase-shifts in response to a single delaying or advancing light pulse in the PER3—/— mouse were not compromised. This demo...
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Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes.
Sleep, 2008Co-Authors: Simon Archer, Malcolm Von Schantz, Antoine U. Viola, Vanessa Kyriakopoulou, Derk-jan DijkAbstract:Study Objectives: Individual sleep timing differs and is governed partly by circadian oscillators, which may be assessed by hormonal markers, or by clock gene expression. Clock gene expression oscillates in peripheral tissues, including leukocytes. The study objective was to determine whether the endogenous phase of these rhythms, assessed in the absence of the sleep-wake and light-dark cycle, correlates with habitual sleep-wake timing. Design: Observational, cross-sectional. Setting: Home environment and Clinical Research Center. Participants: 24 healthy subjects aged 25.0 ± 3.5 (SD) years. Measurements: Actigraphy and sleep diaries were used to characterize sleep timing. Circadian rhythm phase and amplitude of plasma melatonin, cortisol, and BMAL1, PER2, and PER3 expression were assessed during a constant routine. Results: Circadian oscillations were more robust for PER3 than for BMAL1 or PER2. Average peak timings were 6:05 for PER3, 8:06 for PER2, 15:06 for BMAL1, 4:20 for melatonin, and 10:49 for cortisol. Individual sleep-wake timing correlated with the phases of melatonin and cortisol. Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. The correlation between sleep timing and PER3 expression was stronger in individuals homozygous for the variant of the PER3 polymorphism that is associated with morningness. Conclusions: Individual phase differences in PER3 expression during a constant routine correlate with sleep timing during entrainment. PER3 expression in leukocytes represents a useful molecular marker of the circadian processes governing sleep-wake timing.
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A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans
Journal of human genetics, 2006Co-Authors: Jayshan D. Carpen, Malcolm Von Schantz, Marcel Smits, Debra J. Skene, Simon ArcherAbstract:The three PERIOD proteins form a major negative feedback component of the molecular mechanism governing the periodicity of the vertebrate circadian clock. Genetic variations within the human PER2 and PER3 genes have been linked with diurnal preference and disorders of sleep timing. We screened the coding region of PER1, as well as the 5′- and 3′-untranslated regions and the promoter region, for polymorphisms. The T2434C polymorphism in exon 18, a synonymous substitution, associated with extreme diurnal preference. The C allele was more frequent in subjects with extreme morning preference (frequency = 0.24) than in subjects with extreme evening preference (frequency = 0.12). No significant association was observed between either allele and delayed sleep phase syndrome. This polymorphism may have a direct effect on RNA translatability, or be in linkage disequilibrium with another polymorphism which affects PER1 expression at the DNA, RNA, or protein level. This is the first reported association between a PER1 polymorphism and extreme diurnal preference. Functionally important polymorphisms in PER1 are rare, which may indicate that it is subject to more stringent selection pressure than the other PER genes.