Circadian protein TIMELESS regulates synaptic plasticity and memory by modulating cAMP signaling
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ABSTRACT:
PROVIDER: PRJNA858471 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR20169201_1.fastq.gz | Fastqsanger.gz | |||
| SRR20169201_2.fastq.gz | Fastqsanger.gz | |||
| SRR20169202_1.fastq.gz | Fastqsanger.gz | |||
| SRR20169202_2.fastq.gz | Fastqsanger.gz | |||
| SRR20169203_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of circadian genes on cellular and molecular mechanisms that influnce synaptic plasticity and cognitive function remain to be identified. Here, we show that conditional deletion of the circadian gene Timeless in the adult forebrain leads to an impairment in working and fear memory in mice. These cognitive phenotypes were accompanied with LTP attenuation of hippocampal Schaffer-collateral synapses. We discovered TIMELESS protein acts as a transcriptional factor regulating phosphodiesterase 4B (PDE4B) expression. Through Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and fine-tune synaptic plasticity. Our data provide insights into the neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
2023-04-17 | GSE208149 | GEO
Project description:The regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of specific circadian genes on cellular and molecular mechanisms controlling synaptic plasticity and cognitive function remains elusive. Here, we show that the expression of the circadian protein TIMELESS displays circadian rhythmicity in the mammalian hippocampus. We identify TIMELESS as a chromatin-bound protein that targets synaptic-plasticity-related genes such as phosphodiesterase 4B (Pde4b). By promoting Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and influence synaptic plasticity. Conditional deletion of Timeless in the adult forebrain impairs working and contextual fear memory in mice. These cognitive phenotypes were accompanied by attenuation of hippocampal Schaffer-collateral synapse long-term potentiation. Together, these data establish a neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.
| S-EPMC10564971 | biostudies-literature
Project description:Circadian rhythms are present across almost all species and affect several physiological and behavioral aspects of living organisms. The evolutionary advantage conferred by these rhythms could be their anticipatory properties. In the nervous system, anticipation is particularly interesting due to the spatiotemporal constraints derived by the highly compartmentalized neuronal structure. Previous work has confirmed that 900 genes are expressed in the mouse forebrain in robustly rhythmic fashion, and 180 transcripts are equally robustly circadian at the synapse. Interestingly, mRNAs are found in higher amounts at the end of the dark phase, and decrease exponentially during the first hours of light. This pattern resembles the “sawtooth” pattern of homeostatic sleep pressure. To further characterize this phenotype we propose to compare the synaptic transcriptome of sleep deprived mice to its control base line. This work would shed light into the emerging field of synaptic RNA transport and translation and its regulatory inputs. Hopefully, the results will yield to two different findings: the circadian and activity potential to regulate synaptic transport of RNA and the classification of transcripts deferentially regulated by both processes.
2019-02-28 | E-MTAB-7347 | biostudies-arrayexpress
Project description:Circadian and Sleep regulation of synaptic RNA
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Project description:The timing of behavior under natural light-dark conditions is a function of circadian clocks and photic input pathways. Yet a mechanistic understanding of how these pathways collaborate in animals is lacking. Here we demonstrate in Drosophila that the Phosphatase of Regenerating Liver-1 (PRL-1) sets period length and behavioral phase gated by photic signals. PRL-1 knockdown in PDF clock neurons dramatically lengthens circadian period. PRL-1 mutants exhibit allele-specific interactions with the light- and clock-regulated gene timeless (tim). Moreover, we show that PRL-1 promotes TIM accumulation and dephosphorylation. Interestingly, the PRL-1 mutant period lengthening is suppressed in constant light and PRL-1 mutants display a delayed phase under short, but not long, photoperiod conditions. Thus, our studies reveal that PRL-1 dependent dephosphorylation of TIM is a core mechanism of the clock that sets period length and phase in darkness, enabling the behavioral adjustment to changing day-night cycles.
2020-11-11 | PXD020986 | Pride
Project description:Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although circadian rhythms have been implicated in multiple aspects of aging, it remains uncertain whether evolutionary selection of circadian cycle gene variants contributes to changes in longevity and aging traits within animal populations. We have sequenced the genomes of Drosophila melanogaster strains with exceptional longevity that were obtained via multiple rounds of selection for reduced senescence from a parental strain. Preservation of youthful muscle gene expression and function is seen during aging in these strains and is primarily due to intergenic polymorphisms rather than to mutations in coding sequences. Expression of transcriptional regulators of the circadian machinery is highly modulated, with higher period and timeless and lower cycle expression in strains with delayed aging compared to the parental strain. These changes in the expression of circadian core components associate with changes in the amplitude and specificity of the circadian transcriptome. Moreover, a muscle-specific increase in timeless expression to levels similar to long-lived lines extends lifespan. Altogether, these findings indicate that circadian clock gene variants contribute to shaping aging traits and to the evolutionarily divergence in longevity within a species.
2019-06-06 | GSE129922 | GEO
Project description:Abstract Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), a PKA-selective cAMP analog, alters the expression of ~4500 of ~13,600 unique genes. By contrast, gene expression was unaltered in Kin– S49 cells (that lack PKA) incubated with CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements (CRE) within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of CRE-containing genes and secondary networks that include the circadian clock. Keywords: time-course
2005-04-15 | GSE2413 | GEO
Project description:Regions of DNA with the potential to form secondary structure pose a frequent and significant impediment to DNA replication that must be actively countered by cells in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins, comprising Timeless, plays an important role in maintaining efficient replisome function. A previously unappreciated DNA binding domain in the C terminus of Timeless, which exhibits specificity towards G4 structures, acts in collaboration with the DDX11 helicase to ensure replication of G4 structures in vivo and maintenance of genetic and epigenetic stability. Using RNA-seq experiments, we show that (i) Timeless and DDX11 share common gene targets, (ii) the promoter of Timeless- and DDX11-dependent genes are enriched in G4 structures in the vicinity of their promoter and (iii) both Timeless and DDX11 share a common set of gene targets with the FANCJ helicase known to maintain epigenetic stability in the vicinity of G4 structures.
2020-07-01 | GSE139256 | GEO
Project description:There is growing appreciation that the feeling of well-being, alterations in mood and susceptibility to a variety of medical disorders depend on the proper expression of the master circadian clock and the synchrony among the other oscillators found in many peripheral tissues. To improve our understanding of the role of peripheral oscillators, an improved understanding of the molecular machinery sub-serving the circadian variation in gene expression is essential. Our long-term goal is to understand the molecular mechanisms that initiate circadian gene expression following external stimulation in the mammalian pineal gland. Are all or just some of the "circadian clock" genes induced by NE, cAMP, or cGMP? In this project we compare a series of gene expression patterns using DNA microarray in response to cAMP, cGMP and NE stimulation to understand why NE does not initiate circadian rhythms in the rat pineal gland. As a preliminary experiment we will compare gene expression 0, 1, and 4 h after start of chemical stimulation. A failure of NE to initiate circadian rhythms is due to failure of activation of certain "circadian clock" genes. We found that circadian rhythms are initiated by stimulation of cAMP or cGMP analogue in the rat pineal gland, while norepinephrine (NE) stimulation only moderately induce Period1 mRNA (one of "circadian clock" genes) 24 h after start of stimulation. From these results we hypothesize that external stimulation activates some "circadian clock" genes simultaneously, and that failure of circadian rhythm initiation following NE stimulation is due to insufficient "circadian clock" genes activations. Male rats of wistar strain are kept in 12h-12h light dark cycles at least for one week before start of experiments. Pineal glands are removed from animals and placed in the culture dish. Rat pineal glands are cultured for 3 days before chemical stimulation. On the day of experiment, the pineal cultures are stimulated using one of NE, cAMP and cGMP analogues for 1 or 4 h before harvest. The samples are immediately frozen and total RNA are extracted from each group which are from a pool of 8 pineal glands using Trizol reagent (Invitrogen). Concentrations of total RNA are determined using spectrophotometer, and six microgram of total RNA is aliquoted in each sample tube for further analysis. Since we already have Affymetrix Rat Genome U34A array GeneChips, we would like to send Chips as well as our total RNA samples. Experiment Overall Design: as above
2008-06-12 | E-GEOD-2865 | biostudies-arrayexpress
Project description:Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), a PKA-selective cAMP analog, alters the expression of ~4500 of ~13,600 unique genes. By contrast, gene expression was unaltered in Kin- S49 cells (that lack PKA) incubated with CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements (CRE) within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of CRE-containing genes and secondary networks that include the circadian clock.
2007-08-31 | E-GEOD-2413 | biostudies-arrayexpress