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The Nuclear Receptor Rev-erb alpha Regulates Adipose Tissue-Specific FGF21 Signaling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Hee-Woong Lim

PROVIDER: E-GEOD-79166 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling.

Jager Jennifer J Wang Fenfen F Fang Bin B Lim Hee-Woong HW Peed Lindsey C LC Steger David J DJ Won Kyoung-Jae KJ Kharitonenkov Alexei A Adams Andrew C AC Lazar Mitchell A MA

The Journal of biological chemistry 20160321 20

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but no ...[more]

PMID: 27002153

Similar Datasets

The Nuclear Receptor Rev-erb alpha Regulates Adipose Tissue-Specific FGF21 Signaling (Microarray)

Project description:To investigate the role of the transcriptional repressor Rev-erb alpha in epididymal white adipose tissue, we performed a microarray analysis of gene expression in the epididymal white adipose tissue of wildtype and Rev-erb alpha knock-out mice. Examination of the transcriptome in epididymal white adipose tissue of Rev-erb alpha kockout mice compared to wildtype mice.

2016-07-20 | E-GEOD-79164 | biostudies-arrayexpress

The Nuclear Receptor Rev-erb alpha Regulates Adipose Tissue-Specific FGF21 Signaling (ChIP-seq, eWAT)

Project description:The goal of this study is to identify the cistrome of the transcriptional repressor Rev-erb alpha in epididymal white adipose tissue. Performing Rev-erb alpha ChIP-seq on epididymal white adipose tissue from wildtype mice at 5PM when Rev-erb alpha protein level peaks in wild type (WT) mice, we were able to globally determine the genomic regions undergoing Rev-erb alpha-dependent de-repression. Examination of Rev-erb alpha binding in epididymal white adipose tissue.

2016-07-20 | E-GEOD-79165 | biostudies-arrayexpress

Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo

Project description:Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of eRNAs that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed novel mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed new light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ. The goal of this experiment was to determine direct targets of Rev-erb{alpha} in mouse liver. All samples were collected at ZT10, when Rev-erb{alpha} protein levels and genomic binding are maximal. All mice were housed and harvested together (n=5 per genotype). All mice were male, 10-12 week old on C57Bl/6 background. RNA was extracted, processed, and hybridized from each mouse liver individually (each sample represents a single mouse).

2015-01-06 | E-GEOD-59460 | biostudies-arrayexpress

Diurnal changes of HDAC3, Rev-erbα, NCoR and Pol II recruitment to the mouse liver genome and of H3K9Ac

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

The Nuclear Receptor Rev-erb? Regulates Adipose Tissue-specific FGF21 Signaling.

Project description:FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb?, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb? for Rev-erb?-binding sites identified ?Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb? in white adipose tissue but not liver. Rev-erb? ablation led to the robust elevated expression of ?Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erb?. A major Rev-erb?-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ?, which regulates its activity in the opposite direction. These findings establish Rev-erb? as a specific modulator of FGF21 signaling in adipose tissue.

| S-EPMC4865931 | biostudies-literature

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo

Project description:Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2013-01-01 | E-GEOD-42541 | biostudies-arrayexpress

PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis.

Project description:FGF21 is a hormone produced in liver and fat that dramatically improves peripheral insulin sensitivity and lipid metabolism. We show here that obese mice with genetically reduced levels of a key hepatic transcriptional coactivator, PGC-1alpha, have improved whole-body insulin sensitivity with increased levels of hepatic and circulating FGF21. Gain- and loss-of-function studies in primary mouse hepatocytes show that hepatic FGF21 levels are regulated by the expression of PGC-1alpha. Importantly, PGC-1alpha-mediated reduction of FGF21 expression is dependent on Rev-Erbalpha and the expression of ALAS-1. ALAS-1 is a PGC-1alpha target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erbalpha. Modulation of intracellular heme levels mimics the effect of PGC-1alpha on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1alpha. Thus, PGC-1alpha can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand.

| S-EPMC2799738 | biostudies-literature

Regulation of circadian behaviour and metabolism by REV-ERB-? and REV-ERB-?.

Project description:The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-? and REV-ERB-? have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-? has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-? and REV-ERB-? genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-? and REV-ERB-? cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-? and Rev-erb-? function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-? and REV-ERB-? with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.

| S-EPMC3367514 | biostudies-literature

REV-ERB? and REV-ERB? function as key factors regulating Mammalian Circadian Output.

Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERB? and REV-ERB? 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-erb?/Rev-erb? 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 double knockout of both Rev-erb? and Rev-erb? 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-ERB?/? deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.

| S-EPMC6629614 | biostudies-literature

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo (ChIP-Seq)

Project description:We report the genomic regions enriched in Histone Deacetylase 3 (HDAC3) in mouse livers. We also report the change of HDAC3 occupancy upon DAD mutations in NCOR and SMRT. HDAC3 enriched genomic regions in WT and NS-DADm mice livers using Illumina GAIIx.

2013-01-01 | E-GEOD-42540 | biostudies-arrayexpress

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