Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signaling
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123909 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:The human osteosarcoma cell line U2OS contains a functional circadian clock but expresses only a few rhythmic genes. We identified by ChIP-seq analysis 3040 binding sites of the circadian transcription factors BMAL1, CLOCK, and CRY1 in the genome of U2OS cells, comparable to the number found in highly rhythmic tissues like liver. ChIP was performed as described previously (Rey et al, 2011; doi:10.1371/journal.pbio.1000595) using confluent desynchronized U2OS cells and BMAL1, CLOCK, and CRY1-antibodies. Immunoprecipitated chromatin (10 ng DNA of 8 independent BMAL1 ChIPs with enrichment levels > 80-fold, 9 ng DNA of a CRY1 ChIP with 10-fold enrichment, and 8 ng DNA of a CLOCK ChIP with 40-fold enrichment) was used for library preparation. Three lanes of the BMAL1 library, and one lane each of the CRY1 and CLOCK library were sequenced on the Illumina Genome Analyzer IIx using Single-Read Cluster Generation Kit and 36 Cycle Sequencing Kit v2 (Lausanne Genomics Technologies Facility).
2016-02-11 | E-GEOD-44236 | biostudies-arrayexpress
Project description:Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.
2022-07-01 | GSE207271 | GEO
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
Project description:Circadian rhythmicity in renal function suggests a requirement for circadian adaptations in renal metabolism. We studied circadian changes in renal metabolic pathways using integrated transcriptomic, proteomic and metabolomic analysis performed on control mice and mice deficient in the circadian clock gene Bmal1 in the renal tubule (cKOt mice). Proteins were extracted from whole kidneys of 60 mice. Of these, 30 were conditional knockouts of Arntl (Bmal1) and 30 were of control genotype. They were housed under 12-hours light/12-hours dark cycles and were sacrificed at six different time points: zeitgeber time ZT 0, ZT 4, ZT 8, ZT 12, ZT 16, ZT 20 ( ZT 0 being the time of light on and ZT 12 the time of light off). Five replicates per genotype and time point were analysed.
2023-03-15 | PXD036803 | Pride
Project description:Purpose: In this study we employed unbiased, genome-wide techniques to investigate how inflammation-induced NF-kB activation by acute (LPS vs. saline) and chronic (high-fat diet vs. regular chow) environmental stimuli leads to circadian disruption. Methods: We performed ChIP-seq with antibodies directed against the p65 subunit of NF-kB, CLOCK, BMAL1, H3K27Ac and RNA Poll II in livers from mice treated with LPS or saline. ChIP-seq analysis was also performed in livers from mice that were fed high-fat diet for 4 weeks or regular chow. In addition, we performed ChIP-seq with BMAL1 in mouse embryonic fibroblast deficient in p65. Results: Induction of NF-kB reconfigures the genome-wide position of core clock transcription factors. Acute (i.e. LPS) and chronic (e.g. high-fat diet) inflammation-induced NF-kB re-localizes components of the forward limb of clock (CLOCK/BMAL1) to sites convergent with NF-kB and acetylated H3K27 and enriched in RNA POL II in liver. In addition, NF-kB activation leads to higher p65 binding specific to E-box elements within the negative limb of the clock with both acute and chronic stimuli. Conclusions: Our findings cast new light on NF-kB as a pivotal genomic control node integrating metabolic inflammation and circadian systems at both the cellular and organismal levels. In particular, NF-kB directly regulates the expression of the negative limb of the clock while at the same time the clock activator TFs CLOCK/BMAL1 co-localize with NF-kB at new sites to regulate transcription following inflammatory stimuli. In addition, our data indicate significant overlap between NF-kB activation following both acute and chronic inflammatory challenges in liver.
2018-11-20 | GSE117488 | GEO
Project description:The plant pathogenic fungus Verticillium dahliae has homologs of the clock genes [Cascant-Lopez et al., 2020], which are well described in Neurospora crassa [Diernfellner et al., 2020]. In N. crassa, frequency (Frq) and the Frq-interacting RNA helicase (Frh) interact and form the Frq-Frh complex [Cheng et al., 2005]. Formation of this complex was described to be still possible but weakened by a single amino acid exchange of arginine 806 of Frh to histidine (Frh^R806H) [Shi et al., 2010; Conrad et al., 2016]. We found that both FRQ and wild-type FRH were required for enhanced conidiation and the light-dependent repression of microsclerotia formation in V. dahliae, but were dispensable for disease induction in tomato plants. Strikingly, the FRH^R806H mutant strain grew similar to the FRQ deletion strain, although transcript and protein levels of Frq were not significantly affected by the FRH^R806H mutation when compared with the wild-type. Therefore, we hypothesized that V. dahliae Frq and Frh form the Frq-Frh complex to regulate V. dahliae development, and that this complex formation is abolished upon the amino acid exchange in the Frh. By the use of protein pull-downs, potential interactions of Frh-GFP or Frh^R806H-GFP with Frq were investigated. While we found evidence for a direct interaction of Frh-GFP and Frq, no proteins were significantly co-enriched with Frh^R806H-GFP. References: Cascant-Lopez, E.; Crosthwaite, S.K.; Johnson, L.J.; Harrison, R.J. No evidence that homologs of key circadian clock genes direct circadian programs of development or mRNA abundance in Verticillium dahliae. Front Microbiol 2020, 11, 1977, doi:10.3389/fmicb.2020.01977. Diernfellner, A.C.R.; Brunner, M. Phosphorylation timers in the Neurospora crassa circadian clock. J Mol Biol 2020, 432, 3449–3465, doi:10.1016/j.jmb.2020.04.004. Cheng, P.; He, Q.; He, Q.; Wang, L.; Liu, Y. Regulation of the Neurospora circadian clock by an RNA helicase. Genes Dev 2005, 19, 234–241, doi:10.1101/gad.1266805. Shi, M.; Collett, M.; Loros, J.J.; Dunlap, J.C. FRQ-interacting RNA helicase mediates negative and positive feedback in the Neurospora circadian clock. Genetics 2010, 184, 351–361, doi:10.1534/genetics.109.111393. Conrad, K.S.; Hurley, J.M.; Widom, J.; Ringelberg, C.S.; Loros, J.J.; Dunlap, J.C.; Crane, B.R. Structure of the frequency‐interacting RNA helicase: a protein interaction hub for the circadian clock. EMBO J 2016, 35, 1707–1719, doi:10.15252/embj.201694327.
2023-07-12 | PXD041716 | Pride
Project description:Using chromatin immuno-precipitation (ChIP) combined with deep sequencing (ChIP-seq) we obtained a time resolved and genome-wide map of BMAL1 binding in mouse liver, which allowed to identify over two thousand binding sites with peak binding narrowly centered around Zeitgeber time (ZT) 6. Annotation of BMAL1 targets confirms carbohydrate and lipid metabolism as the major output of the circadian clock in mouse liver. Moreover, transcription regulators are largely overrepresented, several of which also exhibit circadian activity. Genes of the core circadian oscillator stand out as strongly bound, often at promoter and distal sites. Genomic sequence analysis of the sites identified E- boxes and tandem E1-E2 consensus elements. Electromobility shift assays (EMSA) showed that E1-E2 sites are bound by a dimer of BMAL1/CLOCK heterodimers with a spacing-dependent cooperative interaction that was further validated in transactivation assays. BMAL1 target genes showed cyclic mRNA expression profiles with a phase distribution centered at ZT10. Importantly, sites with E1-E2 elements showed tighter phases both in binding and mRNA accumulation. Finally, comparing the temporal accumulation of precursor mRNA and mature mRNA helped distinguish direct BMAL1 targets from targets with more complex regulation, and showed how transcriptional and post-transcriptional regulation contribute differentially to circadian expression phase. Together, our analysis of a dynamic protein-DNA interactome uncovered how genes of the core circadian oscillator are wired together and drive phase-specific circadian output programs in a complex tissue. ChIP-Seq of BMAL1 in mouse liver during one circadian cycle at 4 hour time resolution presented in this Series (GSE26602). mRNA profiling data used in this study are already published (Kornmann et al, PLoS Biol 2007) and have been deposited on ArrayExpress repository (accession number: E-MEXP-842).
2011-02-23 | E-GEOD-26602 | biostudies-arrayexpress
Project description:We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.
2020-11-10 | BIOMD0000000975 | BioModels
Project description:The transcription factor BMAL1 is a core element of the circadian clock that contributes to cyclic control of genes transcribed by RNA polymerase II. By using biochemical cellular fractionation and immunofluorescence analyses we reveal a previously uncharacterized nucleolar localization for BMAL1. We used an unbiased approach to determine the BMAL1 interactome by mass spectrometry and identified NOP58 as a prominent nucleolar interactor. NOP58, a core component of the box C/D small nucleolar ribonucleoprotein complex, associates with Snord118 to control specific pre-ribosomal RNA (rRNA) processing steps. These results suggest a non-canonical role of BMAL1 in rRNA regulation. Indeed, we show that BMAL1 controls NOP58-associated Snord118 nucleolar levels and cleavage of unique pre-rRNA intermediates. Our findings identify an unsuspected function of BMAL1 in the nucleolus that appears distinct from its canonical role in the circadian clock system
2020-08-25 | PXD018946 | Pride
Project description:This model is from the article:
Multiple light inputs to a simple clock circuit allow complex biological rhythms
Troein C, Corellou F, Dixon LE, van Ooijen G, O'Neill JS, Bouget FY, Millar AJ.
Plant J.2011 Apr;66(2):375-85.
21219507,
Abstract:
Circadian clocks are biological timekeepers that allow living cells to time their activity in anticipation of predictable environmental changes. Detailed understanding of the circadian network of higher plants, such as Arabidopsis thaliana, is hampered by the high number of partially redundant genes. However, the picoeukaryotic alga Ostreococcus tauri, which was recently shown to possess a small number of non-redundant clock genes, presents an attractive alternative target for detailed modelling of circadian clocks in the green lineage. Based on extensive time-series data from in vivo reporter gene assays, we developed a model of the Ostreococcus clock as a feedback loop between the genes TOC1 and CCA1. The model reproduces the dynamics of the transcriptional and translational reporters over a range of photoperiods. Surprisingly, the model is also able to predict the transient behaviour of the clock when the light conditions are altered. Despite the apparent simplicity of the clock circuit, it displays considerable complexity in its response to changing light conditions. Systematic screening of the effects of altered day length revealed a complex relationship between phase and photoperiod, which is also captured by the model. The complex light response is shown to stem from circadian gating of light-dependent mechanisms. This study provides insights into the contributions of light inputs to the Ostreococcus clock. The model suggests that a high number of light-dependent reactions are important for flexible timing in a circadian clock with only one feedback loop.
Note: Two-gene model of the Ostreococcus circadian clock
This is a model of the circadian clock of Ostreococcus tauri, with a negative feedback loop between TOC1 and CCA1 (a.k.a. LHY) and multiple light inputs. It was used and described in Troein et al., Plant Journal (2011).
The model incorporates luciferase reporters, and in this SBML model the four different versions of the model for transcriptional and translational reporter lines (pTOC1::LUC, pCCA1::LUC, TOC1-LUC and CCA1-LUC) are all accessible by setting one of the rep_X parameters to 1 and the others to 0. You can also set all four to 0 to only simulate the non-reporter core of the system.
Input to the system should be provided by modifying the "light" function. An implementation of LD 12:12 is provided as an example, but the model was also used with more complicated light regimes that vary between data sets and are not convenient to express directly in SBML.
The functions "ox_cca1" and "ox_toc1" can be altered to add overexpression of CCA1 and TOC1. Setting either to x gives additional, constitutive transcription at x times the maximal (and typically not realizable) transcription rate of the native gene. The overexpression mutant fits in Figure 7 of Troein et al. (2011) used ox_cca1 = 0.115 and oc_toc1 = 0.0584, respectively.
The functions "copies_toc1" and "copies_cca1" are normally 1 but can be lowered to simulate knockdown experiments. The functions "transcription", "translation" and "proteasome" can be modified to simulate the effects of altering the overall rate of transcription, translation and protein degradation.
The parameters were fitted specifically to data from transgenic reporter lines TOC8, pTOC3, LHY7 and pLHY7 (Corellou et al., Plant Cell 2009). Parameters that begin with "effcopies" describe the effective number of copies of CCA1 or TOC1 in the respective translational fusion lines, with anything above 1 due to the fusion proteins.
For the model fitting, the initial values were fitted to the data in the various time courses. The initial values given here correspond to the limit cycle of the system in LD 12:12. The system converges to the limit cycle in just a few days under most light conditions, so these initial values are biologically meaningful.
The species cca1luc_c and cca1luc_n have been merged into cca1luc (which corresponds to the observable luminescence signal), because Copasi refused to run the system otherwise. For TOC1-LUC, the predicted output signal is the sum of toc1luc_1 and toc1luc_2.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2011-08-09 | BIOMD0000000350 | BioModels