Regulatory logic of the coupled diurnal and feeding cycles in the mouse liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE60578 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA258563
REPOSITORIES: GEO
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Project description:In mammals, the circadian clock controls behavioral, physiological and cellular rhythms. Part of this daily variation is controlled by transcription-translation feedback loops in sync with the light-dark phase. On the other hand, daily rhythms in expression of a multitude of genes are related to nutrient-response cycles. Time-resolved mapping of DNase I hypersensitive sites (DHS) throughout the day can identify details of the regulatory interplay between metabolism and the internal clock at a molecular level. Here, we report a genome-wide analysis of mammalian DHS using high‐throughput sequencing of DNase tags from mouse liver with a resolution of 4 h (12 h light/12 h dark). Among the 65’000 DHS sites identified, a significant proportion of distal DHS showed a diurnal cycle, suggesting a fine regulation of oscillating genes by enhancers, which we seek to understand better. Using PolII and H3K27ac ChIP-seq, we characterize the DHS and study the dynamics of each mark in wild-type and Bmal1-KO mice. We use the sequence motif content of each DHS and a linear regression model to explain DHS temporal behaviour in terms of phase and amplitude. We monitor the temporal expression of target genes in order to understand the phase-specific regulation in the circadian context. Interestingly, DHS associated with circadian genes tend to be time-correlated with expression, Pol II and H3K27ac marks. The Bmal1-KO phenotype in light-dark conditions show a proportion of DHS with circadian rhythms associated with transcription factors related to metabolism, due to food entrainment and systemic cues.
2016-12-31 | GSE60577 | GEO
Project description:Understanding the kinetics of circadian transcriptional regulation has recently advanced thanks to genome-wide dynamic mapping of RNA Polymerase II, chromatin marks such as histone 3 modifications, and several core clock regulatory factors. To obtain deeper mechanistic insights into the determinant of phase-specific transcription, we here extend previous analyses of the CycliX Consortium by integrating new genome-wide datasets enabling systematic identification of active regulatory regions in the mouse liver. DNase I hypersensitive sites (DHS)-mapping within nuclear chromatin is a powerful method to identify active regulatory elements in the genome. Experiments were performed throughout the diurnal cycle to obtain a temporal map of active regulatory elements. In addition, we quantified H3K27ac, which mark active regulatory regions, throughout the diurnal cycle and RNA Polymerase II using chromatin immunoprecipitation data analysis. DHS were validated as likely regulatory elements by footprinting analyses and overlaps with published ChIP-seq datasets. Analysis of the regions displaying diurnal patterns revealed promoter, transcription start site (TSS)-proximal and TSS-distal elements potentially involved in the regulation of rhythmic gene transcription. Peak phases of DNase I accessibility and H3K27ac levels correlated well with RNA Polymerase II loadings, and regulatory elements oscillated with phases close to those of nearest TSS, which prompted us to use these signals to infer regulatory relationships. Comparisons with results in a Bmal1 -/- genotype (KO) revealed comparable levels of diurnal transcription oscillations likely driven by nutrient and food-entrained rhythms. Using linear modeling, we inferred activities of transcription factors around the clock in WT and KO datasets to reveal that in absence of a functional core circadian clock, FOX transcription factors and glucocorticoid receptor appear to be the main drivers of phase-specific expression. This raises the interesting question of whether light-driven circadian entrainment from the central pacemaker in the SCN acts to counter effect food-related signals.
2016-12-31 | GSE60430 | GEO
Project description:Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver.
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Project description:Diurnal oscillations of gene expression controlled by the circadian clock and its connected feeding rhythm enable organisms to coordinate their physiologies with daily environmental cycles. While available techniques yielded crucial insights into regulation at the transcriptional level, much less is known about temporally controlled functions within the nucleus and their regulation at the protein level. Here, we quantified the temporal nuclear accumulation of proteins and phosphoproteins from mouse liver by SILAC proteomics. We identified around 5,000 nuclear proteins, over 500 of which showed a diurnal accumulation. Parallel analysis of the nuclear phosphoproteome enabled the inference of the temporal activity of kinases accounting for rhythmic phosphorylation. Many identified rhythmic proteins were parts of nuclear complexes involved in transcriptional regulation, ribosome biogenesis, DNA repair, and the cell cycle and its potentially associated diurnal rhythm of hepatocyte polyploidy. Taken together, these findings provide unprecedented insights into the diurnal regulatory landscape of the mouse liver nucleus.
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Project description:DNA methyltransferase 3B (DNMT3B) is critically involved in de novo DNA methylation and genomic stability, while the regulatory mechanism in liver is largely unknown. We previously reported that diurnal variation occurs in the mRNA expression of Dnmt3b in adult mouse liver. The aim of this study was to determine the mechanism underlying the diurnal expression pattern. The highest level and the lowest level of Dnmt3b mRNA expression were confirmed to occur at dawn and in the afternoon, respectively, and the expression pattern of Dnmt3b closely coincided with that of Bmal1. Since the diurnal pattern of Dnmt3b mRNA expression developed at weaning and scheduled feeding to separate the feeding cycle from the light/dark cycle led to a phase-shift in the expression, it could be assumed that feeding plays a critical role as an entrainment signal. In liver-specific Bmal1 knockout (L-Bmal1 KO) mice, L-Bmal1 deficiency resulted in significantly higher levels of Dnmt3b at all measured time points, and the time when the expression was the lowest in wild-type mice was shifted to earlier. Investigation of global DNA methylation revealed a temporal decrease of 5-methyl-cytosine percentage in the genome of wild-type mice in late afternoon. By contrast, no such decrease in 5-methyl-cytosine percentage was detected in L-Bmal1 KO mice, suggesting that altered Dnmt3b expression affects the DNA methylation state. Taken together, the results suggest that the feeding and hepatic clockwork generated by the clock genes, including Bmal1, regulate the diurnal variation in Dnmt3b mRNA expression and the consequent dynamic changes in global DNA methylation.
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Project description:To dissect how diurnal rhythms affect key functions such as transcription or chromatin remodelling, we quantified the temporal nuclear accumulation of proteins and phosphoproteins from mouse liver using in vivo stable isotope labelling by amino acids in cell culture (SILAC)-based mass spectrometry (MS). Protein extracts from isotope labelled mice liver nuclei were used as a reference and mixed with extracts from animals collected every 3 h for 45 h total. Phosphopeptide levels were analysed after enrichment with titanium dioxide (TiO2). The proteins levels were also analysed (dataset with project accession PXD003818).
2016-12-22 | PXD004191 | Pride
Project description:To dissect how diurnal rhythms affect key functions such as transcription or chromatin remodeling, we quantified the temporal nuclear accumulation of proteins and phosphoproteins from mouse liver by SILAC-based MS. Protein extracts from isotope labelled mice liver nuclei were used as a reference and mixed with extracts from animals collected every 3h for 45h total. Total protein levels were analysed together with phosphopeptides after enrichment (see separate dataset for phospho data).
2016-12-09 | PXD003818 | Pride
Project description:This study is a follow up analysis of Tetradesmus obliquus 16:8 hours diurnal cycle experiments, where a starch-less mutant is compared to the wild-type, but this time, in nitrogen limited condition. The samples were collected approximately every 3 hours for both strains (wild-type and starchless mutant). Two time points per condition have two duplicate set (4 samples) because each condition was done in two batches (allowing to take samples during dark period). Overall, this study contain 41 samples, 20 for the wild-type and 21 for the starchless mutant. RNA was extracted for each samples and sent to Novogene for sequencing.
2019-05-30 | E-MTAB-7016 | biostudies-arrayexpress
Project description:Lysine acetylation is involved in various biological processes and is considered a key reversible post-translational modification in the regulation of gene expression, enzyme activity, and subcellular localization. This post-translational modification is therefore highly relevant in the context of circadian biology, but its characterization on the proteome-wide scale and its circadian clock dependence are still poorly described. Here, we provide a comprehensive and rhythmic acetylome map of the mouse liver. Rhythmic acetylated proteins showed subcellular localization-specific phases that correlated with the related metabolites in the regulated pathways. Mitochondrial proteins were over-represented among the rhythmically acetylated proteins and were highly correlated with SIRT3-dependent deacetylation. SIRT3 activity being nicotinamide adenine dinucleotide (NAD)+ level-dependent, we show that NAD+ is orchestrated by both feeding rhythms and the circadian clock through the NAD+ salvage pathway but also via the nicotinamide riboside pathway. Hence, the diurnal acetylome relies on a functional circadian clock and affects important diurnal metabolic pathways in the mouse liver.
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