Circadian clock-mediated neuronal gene expression in Aβ toxicity and excitotoxicity
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ABSTRACT:
PROVIDER: PRJNA849149 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR19648043.fastq.gz | Fastqsanger.gz | |||
| SRR19648045.fastq.gz | Fastqsanger.gz | |||
| SRR19648046.fastq.gz | Fastqsanger.gz | |||
| SRR19648048.fastq.gz | Fastqsanger.gz |
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Project description:In recent decades, transcriptome analysis has been widely used to understand human disease pathogenesis and identify therapeutic targets and biomarkers. Accumulated reports in patients with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, have also provided evidence of dysregulated gene expression related to neuropathogenesis. However, obtaining samples from neurodegenerative patients is more challenging than other human diseases due to low accessibility. Also, brain tissues and cerebrospinal fluid are composed of multiple cell types, so they are unsuitable for obtaining neural cell-type-specific gene expression profiles. Thus, we here report gene expression profiles in primary neuronal cultures exposed to Aβ toxicity and glutamate excitotoxicity to understand pathological gene expression in neurons. By RNA-sequencing analysis, we compare transcriptomes and find that two groups of genes show similar expression patterns in Aβ toxicity excitotoxicity—they are either up- or down-regulated in both conditions. Genes in the two groups are related to synaptic function and cell signaling, which are well-known biological functions altered in Aβ toxicity and excitotoxicity. Interestingly, the analysis reveals a possibility that circadian clock (molecular oscillator generating daily rhythms)-related genes are dysregulated in both conditions. We confirm the reduced circadian transcription factor Bmal1 levels in Aβ toxicity and glutamate excitotoxicity. RNA-sequencing analysis in Bmal1-deleted neurons shows potential relationships between BMAL1 and synaptic functions. Thus, this transcriptome study provides evidence of the potential roles of the circadian clock in neuropathogenesis.
2025-06-14 | GSE206081 | GEO
Project description:The circadian system plays an essential role in regulating timing of body metabolism in humans. Indeed, circadian misalignments are strongly associated with high rates of metabolic disorders. Molecular makeup of the circadian oscillator can be deciphered in cells cultured in vitro, and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo.
We aimed at assessing molecular clock properties in dermal fibroblasts established from the skin biopsies of seventeen Type 2 diabetic obese and non-obese patients and eleven healthy controls. Following in vitro synchronization, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.
We observed a strong inverse correlation between HbA1c values and circadian period length within cells from the Type 2 diabetic group. RNA sequencing analysis conducted in this group samples revealed that ICAM1 encoding for the endothelial adhesion protein was differentially expressed between Type 2 diabetic compensated and non-compensated fibroblasts, and correlated with the period length. Furthermore, ICAM1 expression is driven by rhythmic CLOCK binding.
We provide for the first time a potential molecular link between severity of Type 2 diabetes and circadian clock machinery, which paves a way for further mechanistic understanding of circadian oscillator changes upon Type 2 diabetes in humans.
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Project description:The circadian clock is comprised of proteins that form negative feedback loops, which regulate the timing of global gene expression in a coordinated 24 hour cycle. As a result, the plant circadian clock is responsible for regulating numerous physiological processes central to growth and survival. To date, most plant circadian clock studies have relied on diurnal transcriptome changes to elucidate molecular connections between the circadian clock and observable phenotypes in wild-type plants. Here, we have combined high-throughput RNA-sequencing and mass spectrometry to comparatively characterize the lhycca1, prr7prr9, gi and toc1 circadian clock mutant rosette transcriptome and proteome at the end-of-day and end-of-night.
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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.
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Project description:An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1 abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we investigated how astrocyte activation induced by Bmal1 deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specific Bmal1 knockout mice (Aldh1l1-CreERT2;Bmal1(fl/fl), termed BMAL1 aKO), to the APP/PS1-21 and the APP(NL-G-F) models of Aβ accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aβ. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced by Bmal1 knockout does not influence Aβ deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation.
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Project description:Circadian clocks drive ~24 hr rhythms in tissue physiology. They rely on transcriptional/translational feedback loops driven by interacting networks of clock complexes.To gain insights into the role of the mammary clock, circadian time-series microarrays were performed to identify rhythmic genes in vivo. Breast tissues were isolated at 4 hr intervals for two circadian (24 hourly) cycles, from mice kept under constant darkness to avoid any light- or dark-driven genes.
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Project description:Influence of diet and neuronal clk (clock) activity on hemolymph proteomics. We have shown that as photoreceptors die (in the fly) they necrose, which results in their intercellular contents leaking into the hemolymph. We hypothesize that this process is regulated by diet and circadian clock control.
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