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Thomas P Burris - One of the best experts on this subject based on the ideXlab platform.
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characterization of the core mammalian clock component NPAS2 as a rev erbα rorα target gene
Journal of Biological Chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
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Characterization of the core mammalian clock component, NPAS2, as a REV-ERBα/RORα target gene
The Journal of biological chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
Christine Crumbley - One of the best experts on this subject based on the ideXlab platform.
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characterization of the core mammalian clock component NPAS2 as a rev erbα rorα target gene
Journal of Biological Chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
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Characterization of the core mammalian clock component, NPAS2, as a REV-ERBα/RORα target gene
The Journal of biological chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
Steven L Mcknight - One of the best experts on this subject based on the ideXlab platform.
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NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Paul Franken, Carol A. Dudley, Sandi Jo Estill, Monique T. Barakat, Ryan Thomason, Bruce F. O'hara, Steven L McknightAbstract:Because the transcription factor neuronal Per-Arnt-Sim-type signal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor and an effector of intracellular energy balance, and because sleep is thought to correct an energy imbalance incurred during waking, we examined NPAS2's role in sleep homeostasis using NPAS2 knockout (NPAS2−/−) mice. We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake. Lack of NPAS2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10–15 Hz) was reduced, and within the delta range (1–4 Hz), activity shifted toward faster frequencies. In addition, the increase in the cortical expression of the NPAS2 target gene period2 (per2) after SD was attenuated in NPAS2−/− mice. This implies that NPAS2 importantly contributes to the previously documented wake-dependent increase in cortical per2 expression. The data also revealed numerous sex differences in sleep; in females, sleep need accumulated at a slower rate, and REMS loss was not recovered after SD. In contrast, the rebound in NREMS time after SD was compromised only in NPAS2−/− males. We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed.
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Altered Patterns of Sleep and Behavioral Adaptability in NPAS2-Deficient Mice
Science (New York N.Y.), 2003Co-Authors: Carol A. Dudley, Martin Reick, Paul Franken, Sandi Jo Estill, Claudia Erbel-sieler, Sinae Pitts, Steven L McknightAbstract:Animal behavior is synchronized to the 24-hour light:dark (LD) cycle by regulatory programs that produce circadian fluctuations in gene expression throughout the body. In mammals, the transcription factor CLOCK controls circadian oscillation in the suprachiasmatic nucleus of the brain; its paralog, neuronal PAS domain protein 2 (NPAS2), performs a similar function in other forebrain sites. To investigate the role of NPAS2 in behavioral manifestations of circadian rhythm, we studied locomotor activity, sleep patterns, and adaptability to both light- and restricted food-driven entrainment in NPAS2-deficient mice. Our results indicate that NPAS2 plays a substantive role in maintaining circadian behaviors in normal LD and feeding conditions and that NPAS2 is critical for adaptability to food restriction.
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NPAS2: A Gas-Responsive Transcription Factor
Science (New York N.Y.), 2002Co-Authors: Elhadji M. Dioum, Jared Rutter, Jason R. Tuckerman, Gonzalo Gonzalez, Marie Alda Gilles-gonzalez, Steven L McknightAbstract:Neuronal PAS domain protein 2 (NPAS2) is a mammalian transcription factor that binds DNA as an obligate dimeric partner of BMAL1 and is implicated in the regulation of circadian rhythm. Here we show that both PAS domains of NPAS2 bind heme as a prosthetic group and that the heme status controls DNA binding in vitro. NPAS2-BMAL1 heterodimers, existing in either the apo (heme-free) or holo (heme-loaded) state, bound DNA avidly under favorably reducing ratios of the reduced and oxidized forms of nicotinamide adenine dinucleotide phosphate. Low micromolar concentrations of carbon monoxide inhibited the DNA binding activity of holo-NPAS2 but not that of apo-NPAS2. Upon exposure to carbon monoxide, inactive BMAL1 homodimers were formed at the expense of NPAS2-BMAL1 heterodimers. These results indicate that the heterodimerization of NPAS2, and presumably the expression of its target genes, are regulated by a gas through the heme-based sensor described here.
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regulation of clock and NPAS2 dna binding by the redox state of nad cofactors
Science, 2001Co-Authors: Jared Rutter, Martin Reick, Leeju C Wu, Steven L McknightAbstract:Clock:BMAL1 and NPAS2:BMAL1 are heterodimeric transcription factors that control gene expression as a function of the light-dark cycle. Although built to fluctuate at or near a 24-hour cycle, the clock can be entrained by light, activity, or food. Here we show that the DNA-binding activity of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NADP(H), strongly enhance DNA binding of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized forms inhibit. These observations raise the possibility that food, neuronal activity, or both may entrain the circadian clock by direct modulation of cellular redox state.
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NPAS2: An Analog of Clock Operative in the Mammalian Forebrain
Science (New York N.Y.), 2001Co-Authors: Martin Reick, Carol A. Dudley, Joseph A. Garcia, Steven L McknightAbstract:Neuronal PAS domain protein 2 (NPAS2) is a transcription factor expressed primarily in the mammalian forebrain. NPAS2 is highly related in primary amino acid sequence to Clock, a transcription factor expressed in the suprachiasmatic nucleus that heterodimerizes with BMAL1 and regulates circadian rhythm. To investigate the biological role of NPAS2, we 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 wild-type 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 the circadian cycle in NPAS2-deficient mice. Thus, NPAS2 likely functions as part of a molecular clock operative in the mammalian forebrain.
Colleen A. Mcclung - One of the best experts on this subject based on the ideXlab platform.
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Circadian- and sex-dependent increases in intravenous cocaine self-administration in NPAS2 mutant mice.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Lauren M. Depoy, Ryan W. Logan, Darius Becker-krail, Neha M. Shah, Wei Zong, Kaitlyn Petersen, Jessica H. Brandon, Alyssa M. Miguelino, George C. Tseng, Colleen A. McclungAbstract:Substance use disorder is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and NPAS2 mutant mice at different times of day. In the light (inactive) phase, cocaine reinforcement was increased in all NPAS2 mutants, while self-administration and motivation were affected sex-dependently. These sex differences were amplified during the dark (active) phase with NPAS2 mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and NPAS2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in NPAS2 mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens core and dorsolateral striatum in NPAS2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in NPAS2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of NPAS2 mutation in females.SIGNIFICANCE STATEMENTCircadian disruptions are a common symptom of substance use disorders and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent substance use. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to substance use vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor NPAS2 is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type and NPAS2 mutant mice at different times of day.
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Circadian- and sex-dependent increases in intravenous cocaine self-administration in NPAS2 mutant mice
2019Co-Authors: Lauren M. Depoy, Ryan W. Logan, Darius Becker-krail, Neha M. Shah, Colleen A. McclungAbstract:Abstract Background Addiction is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is highly enriched in reward-related brain regions, but its role in addiction is largely unknown. Methods To examine the role of NPAS2 in reward, we measured intravenous cocaine self-administration in wild-type (WT) and NPAS2 mutant male and female mice at different times of day (light or dark phase). Mice underwent acquisition, dose-response, progressive ratio, extinction and cue-induced reinstatement. Results Cocaine self-administration was elevated in NPAS2 mutant mice, particularly in females. Cocaine reinforcement was increased in all mutant mice, whereas motivation was only increased in females. Sex differences were amplified during the dark (active) phase with NPAS2 mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males. To determine whether circulating ovarian hormones are driving these sex differences we ovariectomized WT and NPAS2 mutant females before cocaine self-administration. Unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are differentially activated in NPAS2 mutant females we measured cocaine-induced ΔFosB expression. ΔFosB expression was increased in D1+ neurons in the nucleus accumbens core and dorsolateral striatum in NPAS2 mutant, relative to WT, females after dark phase self-administration. Conclusions These results suggest NPAS2 regulates reward and cocaine-induced ΔFosB expression in specific striatal regions in a sex and time of day specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of NPAS2 mutation in females.
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Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019Co-Authors: Puja K. Parekh, Ryan W. Logan, Darius Becker-krail, Yanhua H. Huang, Kyle D. Ketchesin, Micah A. Shelton, Mariah A. Hildebrand, Kelly Barko, Colleen A. McclungAbstract:The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of NPAS2 is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that NPAS2 is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of NPAS2 in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using Drd1a-tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of NPAS2 blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of NPAS2 Cell-type-specific NPAS2 knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior.SIGNIFICANCE STATEMENT Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.
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Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure
PloS one, 2013Co-Authors: Edgardo Falcon, Angela R. Ozburn, Shibani Mukherjee, Kole T. Roybal, Colleen A. McclungAbstract:Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (NPAS2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional NPAS2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and NPAS2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2.
Yongjun Wang - One of the best experts on this subject based on the ideXlab platform.
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characterization of the core mammalian clock component NPAS2 as a rev erbα rorα target gene
Journal of Biological Chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
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Characterization of the core mammalian clock component, NPAS2, as a REV-ERBα/RORα target gene
The Journal of biological chemistry, 2010Co-Authors: Christine Crumbley, Yongjun Wang, Douglas J Kojetin, Thomas P BurrisAbstract:The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK (or NPAS2) heterodimers activate the expression of the PERIOD (PER) and CRYPTOCHROME (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK (or NPAS2) completing the feedback loop. The circadian expression of BMAL1 is influenced by retinoic acid receptor-related orphan receptor α (RORα) and REV-ERBα, two nuclear receptors that target a ROR-response element in the promoter of the BMAL1 gene. Given that BMAL1 functions as an obligate heterodimer with either CLOCK or NPAS2, it is unclear how the expression of the partner is coordinated with BMAL1 expression. Here, we demonstrate that NPAS2 is also a RORα and REV-ERBα target gene. Using a ChIP/microarray screen, we identified both RORα and REV-ERBα occupancy of the NPAS2 promoter. We identified two functional ROREs within the NPAS2 promoter and also demonstrate that both RORα and REV-ERBα regulate the expression of NPAS2 mRNA. These data suggest a mechanism by which RORα and REV-ERBα coordinately regulate the expression of the positive arm of the circadian rhythm feedback loop.
