TRAF7 determines circadian period through ubiquitination and degradation of DBP
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Liver
SUBMITTER: 
Hikari Yoshitane
LAB HEAD: Hikari Yoshitane
PROVIDER: PXD051884 | Pride | 2024-08-28
REPOSITORIES: Pride
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Project description:The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. The circadian expressed and clock controlled genes represent about 10% of the transcripts in the mammalian cells, however the role of genome topology in the expression of genes in a circadian manner remains to be elucidated. In this study we investigated the characteristics and dynamics of the genomic loci that contact the clock controlled gene Dbp during the circadian cycle. To do so, we combined genome-wide interaction profiling by chromosome conformation capture-on-chip (4C) technology with analyses of circadian gene expression in synchronized mouse embryonic fibroblasts (MEFs). This approach allowed us to elucidate the three-dimensional organization of the genome during the circadian cycle around the clock controlled gene Dbp, paralleling its circadian expression. We found that the Dbp genomic environment remains largely similar during the circadian cycle. However, specific DNA regions change their frequency of interaction with Dbp as the circadian cycle progresses, delineating a Dbp circadian interactome. These specific changes are not present in Bmal1-/- MEF, suggesting that the clock machinery is implicated in shaping the genomic landscape around the Dbp locus. The Dbp interactome is enriched in DNA elements related to the clock system (E boxes). We found a spatial clustering of functionally related genes. The Dbp circadian interactome contains a subset of circadian genes whose expression closely parallels that for Dbp. Taken together, our results indicate that the Dbp subnuclear environment is organized to privilege the clock directed gene expression program.
2013-08-08 | GSE49582 | GEO
Project description:The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. The circadian expressed and clock controlled genes represent about 10% of the transcripts in the mammalian cells, however the role of genome topology in the expression of genes in a circadian manner remains to be elucidated. In this study we investigated the characteristics and dynamics of the genomic loci that contact the clock controlled gene Dbp during the circadian cycle. To do so, we combined genome-wide interaction profiling by chromosome conformation capture-on-chip (4C) technology with analyses of circadian gene expression in synchronized mouse embryonic fibroblasts (MEFs). This approach allowed us to elucidate the three-dimensional organization of the genome during the circadian cycle around the clock controlled gene Dbp, paralleling its circadian expression. We found that the Dbp genomic environment remains largely similar during the circadian cycle. However, specific DNA regions change their frequency of interaction with Dbp as the circadian cycle progresses, delineating a Dbp circadian interactome. These specific changes are not present in Bmal1-/- MEF, suggesting that the clock machinery is implicated in shaping the genomic landscape around the Dbp locus. The Dbp interactome is enriched in DNA elements related to the clock system (E boxes). We found a spatial clustering of functionally related genes. The Dbp circadian interactome contains a subset of circadian genes whose expression which closely parallel that for Dbp. Taken together, our results indicate that the Dbp subnuclear environment is organized to privilege the clock directed gene expression program. Wild type mouse embryonic fibroblasts at the circadian times (CT) 22, 26, 30, 34 and 46. Bmal1-/- mouse embrionic fibroblasts at CT 22 and CT 34 Biological replicate using an independent line of wild type mouse embrionic fibroblast at CT 22 and CT 34 This submission represents the chromosome conformation capture-on-chip component of the overall study
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Project description:Circadian rhythms are daily physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have long been associated with various neurodegenerative diseases. Abnormal sleep-wake cycle often precedes the onset of cognitive and motor symptoms in patients, while the pathological changes may further exacerbate the disturbance in circadian cycle. It is unclear whether dysregulated circadian rhythm is a consequence of, or a contributing factor for, neurodegeneration. In addition, the evidence directly connecting the neurodegeneration-associated proteins to core circadian clock gene expression remains sparse. Here we show that FUS, a RNA-binding protein implicated in the pathogenesis of ALS and frontotemporal dementia, exhibits a bi-directional regulation with circadian rhythm. Our meta-analysis of RNAseq datasets and subsequent biochemical analysis revealed FUS as a gene regulated by circadian oscillation. Furthermore, NR1D1 binds the FUS promoter and regulates the amplitude of FUS oscillation. Meanwhile, FUS is recruited by transcriptional co-repressor PSF, and is found in the same complex as Bmal-Clock to repress Per2 expression. More strikingly, in cells and brain tissues from homozygous knock-in rats, the pathogenic R521C mutant FUS significantly alters the oscillation patterns of core circadian genes even at young age. Therefore, our results have revealed a novel bi-directional mechanism whereby dysregulated circadian clock and FUS expression may exacerbate neurodegeneration via mutual influence.
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2023-07-18 | GSE237608 | GEO
Project description:The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. However, it remained unclear how this loss of molecular clock oscillation impacted global gene expression and metabolism in cancer, and what benefit cancer cells might gain from suppressing clock oscillation. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, we utilized cells from distinct cancer types with inducible MYC or the closely related N-MYC to determine, using detailed time-series RNA-sequencing and metabolomics, the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter glycosylation while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
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Project description:The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. However, it remained unclear how this loss of molecular clock oscillation impacted global gene expression and metabolism in cancer, and what benefit cancer cells might gain from suppressing clock oscillation. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, we utilized cells from distinct cancer types with inducible MYC or the closely related N-MYC to determine, using detailed time-series RNA-sequencing and metabolomics, the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter glycosylation while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
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