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REV-ERBα influences stability and nuclear localization of the glucocorticoid receptor

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE79087 | GEO | 2016/10/01

SECONDARY ACCESSION(S): PRJNA314897

REPOSITORIES: GEO

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Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

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2012-03-28 | E-GEOD-34019 | biostudies-arrayexpress

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

2012-03-29 | GSE34019 | GEO

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2023-07-12 | GSE236875 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

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

Transcriptomic changes following NR1D1 modulation in thyroid cancer cell lines

Project description:Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as Rev-Erbα, is a circadian clock component that functions as a transcriptional repressor which coordinates circadian rhythm and cell metabolism. Altered circadian clock characteristics have been shown in malignant thyroid neoplasms, and NR1D1 is one of the recurrence-associated genes in papillary thyroid cancer. We aimed to investigate the biological role of NR1D1 in thyroid cancer cells.

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Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBa and REV-ERBb are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erba/Rev-erbb double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the complete knockout of both Rev-erba and Rev-erbb does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBa/b deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study emphasizes REV-ERBs function to form an essential link between the circadian clock and a wide variety of cellular physiological functions.

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2018-02-09 | GSE104129 | GEO

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