Myocardial Rev-erb regulates metabolic diurnal rhythm in heart failure
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE153150 | GEO | 2021/12/08
REPOSITORIES: GEO
Similar Datasets
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
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.
2012-03-29 | GSE34019 | 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.
2012-03-29 | GSE34018 | GEO
Project description:Agonists and antagonists of nuclear receptor Rev-erbα/β, key components of the circadian clock, can benefit the heart. Here, we show that mice with cardiomyocyte-specific knockout (KO) of Rev-erbα/β display progressive cardiac dilation and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. These findings delineate temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism.
2021-09-10 | ST001916 | MetabolomicsWorkbench
Project description:Agonists and antagonists of nuclear receptor Rev-erbα/β, key components of the circadian clock, can benefit the heart. Here, we show that mice with cardiomyocyte-specific knockout (KO) of Rev-erbα/β display progressive cardiac dilation and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. These findings delineate temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism.
2021-09-10 | ST001915 | MetabolomicsWorkbench
Project description:Myocardial Rev-erb regulates metabolic diurnal rhythm in heart failure
| PRJNA641632 | 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:This SuperSeries is composed of the following subset Series: GSE34018: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array] GSE34019: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq] Refer to individual Series
2012-03-28 | E-GEOD-34020 | biostudies-arrayexpress
Project description:We have reported that cold temperature challenge results in a dramatic decrease in levels of the transcriptional repressor, Rev-erb alpha. Performing Rev-erb alpha ChIP-seq on brown adipose from wildtype animals kept at thermoneutrality or cold-challenged (and using Rev-erb alpha KO brown adipose as a control), we were able to globally determine the genomic regions undergoing Rev-erb alpha-dependent de-repression.
2016-12-31 | GSE79167 | GEO
Project description:The nuclear receptors (NRs) REV-ERBα and β, encoded by Nr1d1 and Nr1d2, link circadian rhythms and metabolism. REV-ERB lacks the canonical NR activation domain, and thus functions as a transcriptional repressor. Like other NRs, REV-ERBs can be regulated by ligands, including naturally occurring heme, which potentiate their repressive activity. Attempts to pharmacologically target REV-ERBs by the use of putatively specific synthetic agonists, particularly SR90096, have suggested a wide range of beneficial effects in healthy as well as diseased animal models and cell systems. For instance, Sulli et al. recently reported that REV-ERB activation by SR9009 is specifically lethal to cancer (stem) cells but not other cell types. Because REV-ERBs are core components of the molecular clock, the results were interpreted as a link between the body’s circadian timekeeping system and cancer. Moreover, increased energy expenditure after SR9009 administration decreases obesity in mice, and the reported activity of SR9009 as an exercise mimetic in skeletal muscle have resulted in online sales of the compound as a performance-enhancing drug, with advertisements reassuringly highlighting REV-ERBs as the molecular target (https://www.evolutionary.org/stenabolic-sr9009-review; https://www.simplyanabolics.com/sarms/sr9009-stenabolic/).
2019-05-08 | GSE123312 | GEO