REV-ERBα regulates brain NAD+ levels and neurodegeneration via a brain-specific NFIL3-CD38 -axis
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ABSTRACT:
PROVIDER: PRJNA1077330 | ENA |
REPOSITORIES: ENA
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Project description:Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme which is strongly implicated in the pathogenesis of brain aging and neurodegenerative diseases. Prevention of age-related decline in brain NAD+ levels is an attractive therapeutic strategy for combating age-related neurodegeneration, emphasizing the need to fully understand molecular mechanisms regulating brain NAD+ levels. Previous work has shown that the circadian protein REV-ERBα regulates cellular NAD+ levels in cardiac tissue via control of the NAD+ producing enzyme NAMPT. Whether this pathway regulates brain NAD+ levels, however, is unknown. Here, we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving suppression of the NAD+ consuming enzyme CD38 in astrocytes. Under basal conditions, REV-ERBα suppresses the transcription factor NFIL3 (E4BP4) which itself provides tonic inhibition of CD38 expression, elevating CD38 levels and keeping NAD+ levels low. Deletion of REV-ERBα, either globally or specifically in astrocytes, led to induction of NFIL3, suppression of CD38, increased NAD+, and mitigated protein aggregation, inflammation, and neurodegeneration in a mouse model of tauopathy. This pathway appears to be unique to the brain, as REV-ERBα deletion does not affect NAMPT expression in the brain, does not suppress CD38 in the liver, and has an opposite effect on NAD+ levels in the brain as in the heart. Our data show that the circadian nuclear receptor REV-ERBα can regulate NAD+ via distinct mechanisms in different tissues and define a REV-ERBα-NFIL3-NAD+ downstream pathway controlling brain NAD+ metabolism and neurodegeneration.
2025-06-27 | GSE255975 | GEO
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:Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy
| PRJNA992555 | ENA
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: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: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: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:We evaluated the transcriptional response in the heart upon hepatocyte-specific overexpression of REV-ERBα in the C26 cancer cachexia model.
2025-07-20 | GSE293093 | GEO