Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA992555 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25204629_1.fastq.gz | Fastqsanger.gz | |||
| SRR25204629_2.fastq.gz | Fastqsanger.gz | |||
| SRR25204630_1.fastq.gz | Fastqsanger.gz | |||
| SRR25204630_2.fastq.gz | Fastqsanger.gz | |||
| SRR25204631_1.fastq.gz | Fastqsanger.gz |
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Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
2023-08-09 | PXD043877 | Pride
Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
2023-07-12 | GSE236875 | GEO
Project description:We generated genome-wide cistromes of BAF180 subunit of the SWI-SNF chromatin remodeling complex in mouse liver at CT10 and CT22. In addition, we performed ChIP-Seq analysis on REV-ERBα in WT and SRC-2-/- mouse liver at CT10. We found circadian oscilation of BAF180 chromatin recruitment in mouse liver with peak recruitment at CT22 and nadir at CT10. Further,REV-ERBα chromatin recruitment was significantly reduced in SRC-2-/- mouse liver compared to WT mice at CT10.
2015-12-07 | GSE67852 | GEO
Project description:Myocardial ischemia-reperfusion injury (MIRI) is a major threat to heart functional integrity and pharmacological means to achieve cardioprotection are sorely needed. The sequential hypoxic/normoxic status of the cardiac tissue triggers life-threatening damages through the activation of multiple intra-cellular pathways. Heart tolerance to MIRI varies according to a day-night cycle and is regulated by components of the molecular clock such as the transcriptional repressor and nuclear receptor REV-ERBα. Timed REV-ERBα antagonism alleviates sensitivity to myocardial infarction in mice. Here we show that timed administration of digoxin is cardioprotective by triggering REV-ERBα protein degradation. Kinomics and transcriptomic assays revealed that in several cardiomyocyte cellular models, digoxin and other cardiotonic steroids induced multiple signaling pathways. Pharmacological inhibition and knockdown approaches revealed that inhibition of the Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation, which was fully prevented upon proteasome inhibition. REV-ERBα is increasingly ubiquitinylated in digoxin-treated cells, and its degradation depends on its ability to bind its natural ligand, heme. In unchallenged conditions, the proteasomal degradation of REV-ERBα is controlled by several known (HUWE1, FXW7, SIAH2) or novel (CBL, UBE4B)E3 ubiquitin ligases. Only SIAH2 together with the proteasome subunit PSMB5 were found tocontribute to the digoxin-induced degradation of REV-ERBα. Taken together, these results show that controlling REV-ERBα proteostasis is an appealing cardioprotective strategy, and bring further support to the rationale, timed use of CTS in prophylactic cardiac preconditioning to MIRI.
2022-09-13 | PXD036607 | Pride
Project description:Genome-wide measurements of histone modifications and transcripton factors binding in Lucao35CR PDX tumor and cell models to study FOXA and REV-ERBα regulate the tumorigenic programs
2024-09-25 | GSE260726 | GEO
Project description:Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
| S-EPMC10457319 | biostudies-literature
Project description:We reported a diurnal changes in the recruitment of HDAC3, Rev-erbα, NCoR and Pol II to the mouse liver genome as well as H3K9 acetylation in vivo at ZT10 and ZT22. ChIP-Seq profiling of HDAC3, Rev-erbα, NCoR and Pol II binding and H3K9Ac in mouse liver harvested at 2 different times (ZT10 and ZT22) of the day
2011-03-11 | E-GEOD-26345 | biostudies-arrayexpress
Project description:We report here that REV-ERBα influences nuclear localization of the glucocorticoid receptor and vice versa. As a consequence these two nuclear receptors influence each others transcriptome. REV-ERBα (Nr1d1) is a nuclear receptor that is part of the circadian clock mechanism and regulates metabolism and inflammatory processes. The glucocorticoid receptor (GR, Nr3c1) influences similar processes, but is not part of the circadian clock mechanism although glucocorticoid signaling affects resetting of the circadian clock in peripheral tissues. Because of their similar impact on physiological processes we studied the interplay between these two nuclear receptors. We found that REV-ERBα competes with GR for binding to HSP90, a chaperone responsible for the activation of substrate proteins to ensure survival of a cell. This competition affected stability and nuclear localization of GR, thereby affecting GR target gene expression such as IκB and alcohol dehydrogenase 1 (Adh1). Our findings highlight an important interplay between two nuclear receptors that influence each others transcritpional potential indicating that the transcriptional landscape is strongly dependent on dynamic processes at the protein level.
2016-10-01 | GSE79087 | GEO
Project description:Much of mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors (TF) that comprise molecular clocks. Core clock TFs bind to the genome at non-coding enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. Here we demonstrate that circadian gene expression in mouse liver is controlled by rhythmic chromatin interactions between enhancers and promoters within topologically associating domains (TAD). Rev-erbα-, a core repressive TF of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. These loops are stronger and functionally active in the physiological or genetic absence of Rev-erbα.Thus, a repressive arm of the molecular clock operates by rhythmically interrupting enhancer-promoter loops to control circadian gene transcription.
2018-02-09 | GSE104129 | GEO
Project description:The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erbα has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erbα/β in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism. Identification of Reverb alpha and Reverb beta binding sites in mouse liver at ZT8
2012-03-28 | E-GEOD-34019 | biostudies-arrayexpress