Identification of gene expression changes in sleep mutants associated with reduced longevity in Drosophila
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE148136 | GEO | 2022/01/01
REPOSITORIES: GEO
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Project description:The cellular landscape of most eukaryotic cells changes dramatically over the course of a 24h day. Whilst the proteome responds directly to daily environmental cycles, it is also regulated by a cellular circadian clock that anticipates the differing demands of day and night. To quantify the relative contribution of diurnal versus circadian regulation, we mapped spatiotemporal proteome dynamics under 12h:12h light:dark cycles compared with constant light. Using Ostreococcus tauri, a prototypical eukaryotic cell, we achieved 85% coverage of the theoretical proteome and provided an unprecedented insight into the identity of proteins that drive and facilitate rhythmic cellular functions. Surprisingly, the overlap between diurnally- and circadian-regulated proteins was quite modest (11%). These proteins exhibited different phases of oscillation between the two conditions, consistent with an interaction between intrinsic and extrinsic regulatory factors. The relative amplitude of rhythmic protein abundance was much lower than would be expected from daily variations in transcript abundance. Transcript rhythmicity was poorly predictive of daily variation in abundance of the encoded protein. We observed coordination between the rhythmic regulation of organelle-encoded proteins with the nuclear-encoded proteins that are targeted to organelles. Rhythmic transmembrane proteins showed a remarkably different phase distribution compared with rhythmic soluble proteins, indicating the existence of a novel circadian regulatory process specific to the biogenesis and/or degradation of membrane proteins. Taken together, our observations argue that the daily spatiotemporal regulation of cellular proteome composition is not dictated solely by clock-regulated gene expression. Instead, it also involves extensive rhythmic post-transcriptional, translational, and post-translational regulation that is further modulated by environmental timing cues.
2021-10-28 | PXD025009 | Pride
Project description:Disruption of the circadian clock, which directs rhythmic expression of numerous genes, accelerates aging. To inquire how the circadian system protects organisms during aging, we compared circadian transcriptomes in heads of young and old Drosophila melanogaster. These data revealed a class of genes that adopt de novo rhythmicity during aging, termed "late life cyclers" (LLCs). We show that application of exogenous oxidative stress in young flies mimics aging by inducing robust, rhythmic LLC upregulation in a light- and CLOCK-dependent fashion. Additionally, we identified age-onset rhythmicity in some primary piRNA transcripts that overlap antisense transposable elements. To share our data, we developed a database for public viewing of graphical RNA-seq results for coding and non-coding RNAs in young and old flies. Taken together, our results suggest that aging organisms recruit the circadian system to launch a temporally coordinated defense to cope with their increasingly stressful cellular environments.
2017-01-14 | GSE81100 | GEO
Project description:The circadian clock is an evolutionarily conserved mechanism that drives rhythmic expression of downstream genes. The core circadian clock drives the expression of clock-controlled genes either directly or indirectly, which in turn play critical roles in carrying out many rhythmic physiological processes. Nevertheless, the molecular mechanisms by which clock output genes orchestrate rhythmic signals from the brain to peripheral tissues are largely unknown. Here we explored the role of one rhythmic gene, Achilles, in regulating the rhythmic transcriptome in fly heads. Achilles is a clock-controlled gene in Drosophila that encodes a putative RNA-binding protein. Achilles expression is not detectable in core clock neurons using in-situ hybridization, although its expression is found in neurons throughout the fly brain. Together, these observations argue against a role for Achilles in regulating the core clock. To assess its impact on circadian mRNA rhythms, we performed RNA sequencing (RNAseq) to compare the rhythmic transcriptomes of control flies and those with diminished Achilles expression in all neurons. Consistent with previous observations, we observe dramatic upregulation of immune response genes upon knock-down of Achilles. Furthermore, a subset of circadian mRNAs lose their rhythmicity in Achilles knock-down flies, suggesting that a subset of the rhythmic transcriptome is regulated either directly or indirectly by Achilles. These Achilles-mediated rhythms include many genes involved in immune function and neuronal signaling such as Prosap, Nemy and Jhl-21. Comparison of RNAseq data from control flies reveal that only 42.7% of clock-controlled genes in the fly brain are rhythmic in both males and females. As mRNA rhythms of core clock genes are largely invariant between the sexes, this observation suggests that sex-specific mechanisms are an important, and heretofore under-appreciated, regulator of the rhythmic transcriptome.
2018-12-31 | GSE120100 | GEO
Project description:Background: Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals suffering with these illnesses also have major disruptions in sleep and circadian rhythms, and disturbances to sleep and circadian rhythms can precipitate or exacerbate psychotic symptoms. Psychosis is associated with the striatum, though no study to date has directly measured molecular rhythms and determined how they are altered in the striatum of subjects with psychosis. Methods: Here, we perform RNA-sequencing and both differential expression and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (NAc, caudate, and putamen) in subjects with psychosis relative to unaffected comparison subjects. Results: Across regions, we find differential expression of immune-related transcripts and a substantial loss of rhythmicity in core circadian clock genes in subjects with psychosis. In the nucleus accumbens (NAc), mitochondrial-related transcripts have decreased expression in psychosis subjects, but only in those who died at night. Additionally, we find a loss of rhythmicity in small nucleolar RNAs and a gain of rhythmicity in glutamatergic signaling in the NAc of psychosis subjects. Between region comparisons indicate that rhythmicity in the caudate and putamen is far more similar in subjects with psychosis than in matched comparison subjects. Conclusions: Together, these findings reveal differential and rhythmic gene expression differences across the striatum that may contribute to striatal dysfunction and psychosis in psychotic disorders.
2022-08-31 | GSE202537 | GEO
Project description:The circadian clock and rhythmic food intake are both important regulators of rhythmic gene expression in the liver. It remains, however, elusive to which extent the circadian clock network and natural feeding rhythms contribute to rhythmic gene expression. To systematically address this question, we developed an algorithm to investigate differential rhythmicity between a varying number of conditions. Mouse knockout models of different parts of the circadian clock network (Bmal1, Cry1/2, and Hlf/Dbp/Tef) exposed to controlled feeding regimens (ad libitum, night restricted feeding) were generated and analyzed for their temporal hepatic transcriptome. A genetical ablation of core loop elements altered feeding patterns that were restored by night restricted feeding. Mainly genes with a high amplitude were driven by the circadian clock but natural feeding patterns equally contributed to rhythmic gene expression with lower amplitude. We observed that Bmal1 and Cry1/2 KOs differed in rhythmic gene expression and identified differences in mean expression levels as a predictor for rhythmic gene expression. In Hlf/Dbp/Tef KO, mRNA levels of Hlf/Dbp/Tef target genes were decreased, albeit rhythmicity was overall preserved potentially due to the activity of the D-Box binding repressor NFIL3. Genes that lost rhythmicity in Hlf/Dbp/Tef KOs were identified to be no direct targets of PARbZip factors and presumably lost rhythmicity due to indirect effects. Collectively, our findings provide unprecedent insights into the diurnal transcriptome in mouse liver and defines the contribution of subloops of the circadian clock network and natural feeding cycles. The developed algorithm and a webapp to browse the outcomes of the study are publicly available to serve as a resource for the scientific community.
2020-12-03 | GSE135898 | GEO
Project description:The circadian clock and rhythmic food intake are both important regulators of rhythmic gene expression in the liver. It remains, however, elusive to which extent the circadian clock network and natural feeding rhythms contribute to rhythmic gene expression. To systematically address this question, we developed an algorithm to investigate differential rhythmicity between a varying number of conditions. Mouse knockout models of different parts of the circadian clock network (Bmal1, Cry1/2, and Hlf/Dbp/Tef) exposed to controlled feeding regimens (ad libitum, night restricted feeding) were generated and analyzed for their temporal hepatic transcriptome. A genetical ablation of core loop elements altered feeding patterns that were restored by night restricted feeding. Mainly genes with a high amplitude were driven by the circadian clock but natural feeding patterns equally contributed to rhythmic gene expression with lower amplitude. We observed that Bmal1 and Cry1/2 KOs differed in rhythmic gene expression and identified differences in mean expression levels as a predictor for rhythmic gene expression. In Hlf/Dbp/Tef KO, mRNA levels of Hlf/Dbp/Tef target genes were decreased, albeit rhythmicity was overall preserved potentially due to the activity of the D-Box binding repressor NFIL3. Genes that lost rhythmicity in Hlf/Dbp/Tef KOs were identified to be no direct targets of PARbZip factors and presumably lost rhythmicity due to indirect effects. Collectively, our findings provide unprecedent insights into the diurnal transcriptome in mouse liver and defines the contribution of subloops of the circadian clock network and natural feeding cycles. The developed algorithm and a webapp to browse the outcomes of the study are publicly available to serve as a resource for the scientific community.
2020-12-03 | GSE135875 | GEO
Project description:Purpose: Circadian clock in plants temporally coordinates biological processes throughout the day synchronizing gene expression with environmental changes. Here, we examined the genome-wide circadian and diurnal control of Arabidopsis transcriptome using high throughout RNA-seq approach. Methods: Transcriptional and posttranscritional profiles were identified and characterized for Arabidopsis seedlings grown under continuous light or long-day condition (16 h light/8 h dark) for one day (each condition has two biological replicates). Results: We show that rhythmic posttranscriptional regulation is also a significant factor for genome-wide profile of circadian plant transcriptome. Two major posttranscriptioal mechanisms alternative splicing (AS) and alternative polyadenylation (APA) show circadian rhythmicity, resulting from the oscillation in the genes invovled in AS and APA. Conclusions: Arabidopsis circadian clock not only controls the transcription of genes, but also affects their posttranscriptional regulation through regulating AS and APA.
2020-01-14 | GSE137732 | GEO
Project description:With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here we employed a previously-described time-of-death analyses to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex (Brodmann’s areas (BA) 11 and 47). Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ~10% of detected transcripts (p<0.05). Using a meta-analysis across the two brain areas, we identified a core set of 235 genes (q<0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than one thousand genes (1186 in BA11; 1591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep and mood in later life.
2015-12-31 | GSE71620 | 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. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. 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, cells from distinct cancer types with inducible MYC or the closely related N-MYC were examined, using detailed time-series RNA-sequencing and metabolomics, to determine 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 proteins 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.
2023-07-18 | GSE237608 | GEO
Project description:Virtually every mammalian tissue exhibits rhythmic expression in thousands of genes, which activate tissue-specific processes at appropriate times of the day. Much of this rhythmic expression is thought to be driven cell-autonomously by molecular circadian clocks present throughout the body. However, increasing evidence suggests that systemic signals, and more specifically rhythmic food intake (RFI), can regulate rhythmic gene expression independently of the circadian clock. To determine the relative contribution of cell autonomous clocks versus RFI in the regulation of rhythmic gene expression, we developed a system that allows long-term manipulation of the daily rhythm of food intake in the mouse, and analyzed liver gene expression by RNA-Seq in mice fed ad libitum, only at night, or arrhythmically (mouse eating 1/8th of their daily food intake every 3 hours). We show that 70% of the cycling mouse liver transcriptome loses rhythmicity under arrhythmic feeding. Remarkably, this loss of rhythmic gene expression under arrhythmic feeding is independent of the liver circadian clock, which continues to exhibit normal oscillations in core clock gene expression. Many genes that lose rhythmicity participate in the regulation of metabolic processes such as lipogenesis and glycogenesis, likely contributing to an increased sensitivity to insulin that was observed in arrhythmically-fed mice. We also show that night-restricted feeding significantly increases the number of rhythmically expressed genes as well as the amplitude of the rhythms. Together, these results indicate that metabolic transcription factors control a large fraction of the rhythmic mouse liver transcriptome, and demonstrate that systemic signals driven by rhythmic food intake play a more important role than the cell-autonomous circadian clock in driving rhythms in liver gene expression and metabolic functions.
2019-04-25 | GSE118967 | GEO