Familial Advanced Sleep Phase (FASP) is a heritable human sleep phenotype characterized by very early sleep and wake times. We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene ...that co-segregates with FASP in one family. The mutation leads to replacement of an alanine residue at position 260 with a threonine (A260T). In mice, the CRY2 mutation causes a shortened circadian period and reduced phase-shift to early-night light pulse associated with phase-advanced behavioral rhythms in the light-dark cycle. The A260T mutation is located in the phosphate loop of the flavin adenine dinucleotide (FAD) binding domain of CRY2. The mutation alters the conformation of CRY2, increasing its accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus promoting its degradation. These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior.
Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with ...poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β1-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1+ neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β1-adrenergic receptors in sleep/wake regulation.
•A mutation in ADRB1 leads to natural short sleep trait in humans•Mice engineered with same mutation have similar short sleep behavior as humans•Activity of dorsal pons ADRB1+ neurons associates with REM sleep and wakefulness•Mutation increases the population activity of dorsal pons ADRB1+ neurons
A mutation in ADRB1 was found in humans who sleep fewer hours than most. Using mouse modeling and calcium imaging experiments, Shi et al. demonstrate that dorsal pons ADRB1+ neuron activity is increased in the mutant, correlating with increased wakefulness.
Many animals display morning and evening bimodal activities in the day/night cycle. However, little is known regarding the potential components involved in the regulation of bimodal behavioral ...rhythms in mammals. Here, we identified that the zinc finger protein gene
plays a crucial role in the regulation of bimodal activities in mice. Depletion of
in nerve system resulted in the loss of early evening activity, but the increase of morning activity. We found that
-deficient mice exhibited a pronounced decrease in the expression of
and resembled phenotypes of
and
-knockout mice. Injection of adeno-associated virus-double-floxed
in suprachiasmatic nucleus could partly restore evening activity in
(NS-ZB20KO) mice. Furthermore, loss of
in
loci, but intact in the suprachiasmatic nucleus, was not responsible for the unimodal activity of NS-ZB20KO mice. Our study provides evidence that ZBTB20-mediated PROKR2 signaling is critical for the evening behavioral rhythms.
Circadian clocks allow organisms to orchestrate the daily rhythms in physiology and behaviors, and disruption of circadian rhythmicity can profoundly affect fitness. The mammalian circadian ...oscillator consists of a negative primary feedback loop and is associated with some 'auxiliary' loops. This raises the questions of how these interlocking loops coordinate to regulate the period and maintain its robustness. Here, we focused on the REV-ERBα/Cry1 auxiliary loop, consisting of Rev-Erbα/ROR-binding elements (RORE) mediated Cry1 transcription, coordinates with the negative primary feedback loop to modulate the mammalian circadian period. The silicon simulation revealed an unexpected rule: the intensity ratio of the primary loop to the auxiliary loop is inversely related to the period length, even when post-translational feedback is fixed. Then we measured the mRNA levels from two loops in 10-mutant mice and observed the similar monotonic relationship. Additionally, our simulation and the experimental results in human osteosarcoma cells suggest that a coupling effect between the numerator and denominator of this intensity ratio ensures the robustness of circadian period and, therefore, provides an efficient means of correcting circadian disorders. This ratio rule highlights the contribution of the transcriptional architecture to the period dynamics and might be helpful in the construction of synthetic oscillators.
Organization of circadian behavior, physiology, and metabolism is important for human health. An S662G mutation in hPER2 has been linked to familial advanced sleep-phase syndrome (FASPS). Although ...the paralogous phosphorylation site S714 in PER1 is conserved in mice, its specific function in circadian organization remains unknown. Here, we find that the PER1S714G mutation accelerates the molecular feedback loop. Furthermore, hPER1S714G mice, but not hPER2S662G mice, exhibit peak time of food intake that is several hours before daily energy expenditure peaks. Both the advanced feeding behavior and the accelerated clock disrupt the phase of expression of several key metabolic regulators in the liver and adipose tissue. Consequently, hPER1S714G mice rapidly develop obesity on a high-fat diet. Our studies demonstrate that PER1 and PER2 are linked to different downstream pathways and that PER1 maintains coherence between the circadian clock and energy metabolism.
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•S714G mutation in PER1 causes internal clock misalignment•S714G mutation in PER1 is associated with feeding rhythms•PER1S714G mice rapidly develop obesity•PER1 is an important regulator of interactions between clock and energy metabolism
Loss-of-function mutations have revealed how clock components generate 24 hr rhythms. However, the mechanisms that ensure timing of sleep and metabolism in a 24 hr day are unclear. A missense mutation at a phosphorylation site in the clock component Period2 advances sleep onset and causes advanced-phase syndrome. In this study, Liu et al. find that an equivalent mutation in human Period1 mistimes feeding and predisposes to obesity in mice. Hence, posttranslational modifications of clock components orchestrate timing of behavior, metabolism, and physiology.
Many aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism, are under precise control by the mammalian circadian clock. However, the molecular ...mechanism for coordinate integration of the circadian clock and various metabolic pathways is poorly understood. Here we show that BAF60a, a chromatin‐remodeling complex subunit, is rhythmically expressed in the liver of mice. Mice with liver‐specific knockdown of BAF60a show abnormalities in the rhythmic expression pattern of clock and metabolic genes and in the circulating metabolite profile. Consistently, knockdown of BAF60a impairs the oscillation of clock genes in serum‐shocked HepG2 cells. At the molecular level, BAF60a activates Bmal1 and G6Pase transcription by way of the coactivation of retinoid‐related orphan receptor alpha (RORα). In addition, BAF60a is present near ROR response elements (RORE) on the proximal Bmal1 and G6Pase promoters and turns the chromatin structure into the active state. Conclusion: Our data suggest a critical role for BAF60a in the coordinated regulation of hepatic circadian clock and energy metabolism in mammals. (HEPATOLOGY 2011;)
The mammalian circadian clock is composed of interlocking feedback loops. Cryptochrome is a central component in the core negative feedback loop, whereas Rev-Erbα, a member of the nuclear receptor ...family, is an essential component of the interlocking loop. To understand the roles of different clock genes, we conducted a genetic interaction screen by generating single- and double-mutant mice. We found that the deletion of Rev-erbα in F-box/leucine rich-repeat protein (Fbxl3)-deficient mice rescued its long-circadian period phenotype, and our results further revealed that FBXL3 regulates Rev-Erb/retinoic acid receptor-related orphan receptor-binding element (RRE)-mediated transcription by inactivating the Rev-Erbα:histone deacetylase 3 corepressor complex. By analyzing the Fbxl3 and Cryptochrome 1 double-mutant mice, we found that FBXL3 also regulates the amplitudes of E-box–driven gene expression. These two separate roles of FBXL3 in circadian feedback loops provide a mechanism that contributes to the period determination and robustness of the clock.
In the core mammalian circadian negative feedback loop, the BMAL1-CLOCK complex activates the transcription of the genes Period (Per) and Cryptochrome (Cry). To close the negative feedback loop, the ...PER-CRY complex interacts with the BMAL1-CLOCK complex to repress its activity. These two processes are separated temporally to ensure clock function. Here, we show that histone deacetylase 3 (HDAC3) is a critical component of the circadian negative feedback loop by regulating both the activation and repression processes in a deacetylase activity-independent manner. Genetic depletion of Hdac3 results in low-amplitude circadian rhythms and dampened E-box-driven transcription. In subjective morning, HDAC3 is required for the efficient transcriptional activation process by regulating BMAL1 stability. In subjective night, however, HDAC3 blocks FBXL3-mediated CRY1 degradation and strongly promotes BMAL1 and CRY1 association. Therefore, these two opposing but temporally separated roles of HDAC3 in the negative feedback loop provide a mechanism for robust circadian gene expression.
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•HDAC3 is a critical component of the core mammalian circadian negative feedback loop•HDAC3 is required for efficient activation of E-box-driven gene expression•HDAC3 blocks CRY1 degradation and promotes BMAL1 and CRY1 association•Temporal separation of these opposing roles ensures robust circadian gene expression
Shi et al. report a deacetylase-independent function of HDAC3 in maintaining a robust circadian clock. HDAC3 modulates the function of several key components of the clock machinery and affects both the activation and suppression of transcription in the circadian cycle.
Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated ...the role of different NPS
nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS
neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS
neurons are not important for sleep/wake modulation. Further, we found that a NPS
nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS
neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS-NPSR1 signaling or knockdown of
supported the function of the NPS-NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS
neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.
Human genetics and sleep behavior Shi, Guangsen; Wu, David; Ptáček, Louis J ...
Current opinion in neurobiology,
06/2017, Letnik:
44
Journal Article
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Highlights • Human genetics offers essential insight into the characterization of sleep. • Genetic polymorphisms impact sleep timing, duration, and architecture. • A bi-directional relationship ...exists between sleep and healthy brain.
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