Nutrient Abundance Signals the Changing of the Seasons by Phosphorylating PER2
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254155 | GEO | 2024/01/29
REPOSITORIES: GEO
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Project description:Circadian rhythms are a series of endogenous autonomous 24-hour oscillations generated by the circadian clock. At the molecular level, the circadian clock is generated by a transcription-translation feedback loop, where BMAL1 and CLOCK transcription factors of the positive arm activate the expression of CRYPTOCHROME and PERIOD (PER) genes of the negative arm as well as the circadian clock-regulated genes. In this project, we aimed at finding the interactome of PER2 protein in human U2OS osteosarcoma cell line using proximity-dependent biotin identification (BioID) technique. U2OS clones overexpressing PER2-BioID2 or BioID2 were treated with dexamethasone in order to reset the circadian rhythm, and cells were then incubated in biotin-containing media for 12 hours to label the proteins in close proximity of PER2-BioID2. Samples were collected after 36 and 48 hours of the resetting to identify the labeled proteins by mass spectrometry. In addition to known interactors such as CRY1 and CRY2, many novel interactors were identified. In summary, we obtained a network of PER2 interactome and confirmed some of the novel interactions using classical the co-immunoprecipitation method.
2022-04-22 | PXD025179 | Pride
Project description:Circadian clocks coordinate time-of-day specific metabolic and physiological processes to maximize performance and fitness. In addition to light, which is considered the strongest time cue to entrain animal circadian clocks, metabolic input has emerged as an important signal for clock modulation and entrainment, especially in peripheral clocks. Circadian clock proteins have been to be substrates of O-GlcNAcylation, a nutrient sensitive post-translational modification (PTM), and the interplay between clock protein O-GlcNAcylation and other PTMs, like phosphorylation, is expected to facilitate the regulation of circadian physiology by metabolic signals. Here, we used mass spectrometry proteomics to identify PTMs on PERIOD, the key biochemical timer of the Drosophila clock, over the circadian cycle.
2017-11-23 | MSV000081736 | MassIVE
Project description:With the exception of latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet, investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to light duration at the equator. Here, we hypothesised that altering seasonal photoperiod affects both rhythmicity of peripheral tissue clocks as well as processes involved in energy storage and utilisation. Male mice were housed at one of three photoperiods representing light hours in summer, winter and the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin proficient and deficient mice, we provide evidence that the effect of seasonal light on energy metabolism is largely driven by differences in the rhythmicity of food intake, but not melatonin. Our results show that seasonal light impacts energy metabolism in mice and suggest that these effects are partly driven by modulating the timing of eating. Our work sets a course to integrate seasonal light duration in future circadian biology studies.
2023-09-09 | GSE222550 | GEO
Project description:We show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock via phosphorylation of PER2. CDK5 phosphorylated PER2 at serine residue 394 (S394) as shown by an in vitro kinase assay.
2019-12-04 | PXD012068 | Pride
Project description:The peripheral circadian oscillator plays an essential role in synchronizing local physiology to operate in a circadian manner via regulation of the expression of clock-controlled genes. In the murine uterus, the endometrial stromal cells undergo proliferation and differentiation into decidual cells in response to ovarian steroids and blastocyst implantation at the early stage of pregnancy. The circadian clock genes are attenuated in the decidualizing cells only 2 days after implantation. The present study aimed to evaluate the circadian rhythms of clock genes and clock-controlled genes expressed in the rat uterus endometrial stromal cells (UESCs) during the stage of implantation. The real-time monitoring system of Per2 promoter activity was employed to precisely evaluate the generation of circadian rhythms in the UESCs prepared from transgenic rats constructed with mouse Per2 promoter-destabilized luciferase reporter gene (Per2-dLuc). During monitoring Per2-dLuc oscillation after synchronization with dexamethasone, total RNA was isolated from the cultured UESCs at four-time points (6-h interval) in the first to second phases and cDNA was synthesized. cRNA was synthesized from the double strand cDNA and hybridized on a DNA microarray. RT-qPCR was performed to confirm the expression of core clock genes revealed by DNA microarray analysis. Several clock genes such as Bmal1, Rev-erbα, and Per2 displayed significant rhythms. Of 12,252 genes showing significantly expression, 7,235 genes displayed significant alterations (p < 0.05). These genes were related to growth factors, transcription factors, receptors, channels, and enzymes. Some candidates as clock-controlled genes were evaluated by using RNA interference to Bmal1 mRNA. Down-regulation of Igf1 gene expression was observed by Bmal1 silencing, whereas the expression of Inhβa, Fas, and Caspase3 were significantly increased. These results indicate that clock-controlled genes are up- or down-regulated in rat UESCs during the stage of decidualization. DNA microarray analysis coupled with RNA interference will be helpful to understand the physiological roles of some oscillating genes in blastocyst implantation and placenta formation. The circadian clock positively or negatively regulates the expression of clock-controlled genes, including growth factors and apoptosis-related factors. To search the clock-controlled genes expressed during the period of implantation, we analyzed the clock genes and clock-controlled genes expressed in cultured uterus endometrial stromal cells prepared from pregnant rats at the stage of implantation using DNA microarray technology. We used transgenic rats constructed with mouse Per2 promoter-destabilized luciferase (Per2-dLuc) reporter gene to precisely adjust the time of gene expression. In addition, several genes of significantly expressed genes including growth factor genes and apoptosis-related genes were analyzed using RNA interference to Bmal1 mRNA whether these were controlled under circadian clockwork.
2013-07-23 | E-GEOD-49080 | biostudies-arrayexpress
Project description:SIRT1 is involved in both aging and circadian clock regulation, yet the link between the two processes in relation to SIRT1 function is unclear. Analyzing SIRT1-deficient cells and mice, we demonstrated that SIRT1 and Per2 constitute a reciprocal negative regulation loop that plays important roles in modulating circadian rhythmicity, metabolism and aging. SIRT1-deficient mice exhibit profound premature aging and enhanced H4K16 acetylation in the promoter of Per2 leading to its overexpression; in turn, Per2 suppresses SIRT1 transcription through binding to SIRT1 promoter at the CLOCK/BMAL1 site. We further demonstrated that absence of SIRT1 or ectopic overexpression of Per2 in the liver resulted in an accelerated pace of circadian rhythm and dysregulated amplitude, mimicking the natural process of circadian shortening in aged mice. Thus the interplay between SIRT1 and Per2 provides a link between the life-long sequence of aging and circadian clock maintenance.
2016-08-08 | GSE54449 | GEO
Project description:Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. To investigate hepatic SIRT1-dependent aging related genes, livers from wild type mice at 3 months (young), 12 months (middle age), and 19 months (old) of age, as well as Sirt1-deficient mice at 3 months of age were snap frozen and subject to RNA isolation and microarray analysis.
2016-08-08 | E-GEOD-54436 | biostudies-arrayexpress
Project description:Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.
2016-08-08 | GSE54436 | GEO
Project description:Implantation is dependent on synchronized interactions between the conceptus and surrounding decidual cells but the involvement of clock genes in this process is not well understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK and BMAL1 and repressors encoded by PER and CRY genes. Here we show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Downregulation was preceded by reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter and occurred between 12 - 24 h after exposure to a deciduogenic stimulus. RNA sequencing revealed that premature inhibition of PER2 by siRNA knockdown leads to a grossly disorganised decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators amongst the 1,121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of mid-luteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure. Thus, PER2 synchronizes mitotic expansion of HESCs with a periodic decidual gene expression; uncoupling of these events may cause persistent pregnancy failure. Endometrial mRNA profiles of paired control (siRNA-NT) and siRNA-PER2 were generated by deep sequencing, in triplicate using Illumina
2015-09-16 | E-GEOD-62854 | biostudies-arrayexpress
Project description:Seasonal adaptation to changes in light:dark regimes (i.e., photoperiod) allows organisms living at temperate latitudes to anticipate environmental change and adjust their physiology and behavior accordingly. The circadian system has been implicated in measurement and response to changes in photoperiod in nearly all animals studied so far (Saunders, 2011). The use of both traditional and non-traditional model insects with robust seasonal responses has recently genetically demonstrated the central role that clock genes play in photoperiodic response. Yet, the molecular pathways involved in insect photoperiodic responses remain largely unknown. Here, using the Eastern North American monarch butterfly (Reppert et al, 2016; Denlinger et al, 2017), we identified the vitamin A pathway as a novel pathway downstream of the circadian clock mediating insect photoperiod responsiveness. We found that interrupting clock function by disrupting circadian activation and repression abolishes photoperiodic responses in reproductive output, providing a functional link between clock genes and photoperiodic responsiveness in the monarch. Through transcriptomic approaches, we identified a molecular signature of seasonal-specific rhythmic gene expression in the brain, the organ known to function in photoperiodic reception in both Lepidoptera and some flies (Bowen et al, 1984; Saunders & Cymborowski, 1996). Among genes differentially expressed between both long and short photoperiods and between seasonal forms, several were belonging to the vitamin A pathway. The rhythmic expression of all of these genes was abolished in clock-deficient mutants. We also showed that a CRISPR/Cas9-mediated loss-of-function mutation in the pathway’s rate-limiting enzyme, ninaB1, impaired the monarch ability to respond to the photoperiod independently of visual function in the compound eye and without affecting circadian rhythms. Our finding that the vitamin A pathway is a key mediator of photoperiodic responses in insects could have broad implications for understanding the molecular mechanisms underlying photoperiodism.
2019-11-13 | GSE126336 | GEO