Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

Step, Sonia E.; Lim, Hee‐Woong; Marinis, Jill M.; Prokesch, Andreas; Steger, David J.; You, Seo-Hee; Won, Kyoung Jae; Lazar, Mitchell A.

doi:10.1101/gad.237628.114

Cited by 89 publications

(101 citation statements)

References 66 publications

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“…It is possible that LPS maximizes inflammatory responses by redistributing TFs that are required to transcribe genes involved in normal cellular metabolism in a resting condition to SEs that mark functionally relevant proinflammatory genes. Thus, the decrease in transcriptional levels might be due to either a loss or redistribution of these TFs or, as previously shown in other systems, a sequestering of TFs (14,29,30,33). Further studies are needed to address this issue.…”

Section: Resultsmentioning

confidence: 91%

“…However, most studies focused mainly on the functions of enhancers and eRNAs in transcriptional activation, whereas signal-dependent transcriptional repression has not been directly addressed in the context of enhancer function. Recent studies have demonstrated that signaling through nuclear receptors such as ER and peroxisome proliferator-activated receptor can cause release of coactivators at enhancers, resulting in repression of gene expression (14,29,30). However, the contribution of eRNA repression, if any, to this process remains unknown.…”

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confidence: 99%

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Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

Hah

Benner

Chong³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

138

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Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.super enhancers | enhancer RNAs | transcription factors | GRO-Seq | macrophage

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Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 99%

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

Hah

Benner

Chong³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

138

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“…5B). Moreover, analysis of GRO-seq in 3T3-L1 adipocytes (46) revealed that transcription at both the Klb gene body and the most transcription start site-proximal enhancer was increased as early as 10 min after addition of rosiglitazone (rosi), a potent synthetic agonist ligand of PPAR␥ (Fig. 5C).…”

Section: Resultsmentioning

confidence: 99%

“…The y axis scale refers to the normalized tag count per million reads. C, GRO-seq was performed in 3T3-L1 adipocytes treated with rosiglitazone (Rosi) for 10 min or left untreated (46). Genome browser views of nascent transcripts at the Klb locus are shown.…”

Section: Resultsmentioning

confidence: 99%

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

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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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 Reverb␣. 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.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

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WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

et al. 2020

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White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT‐type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high‐fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole‐body glucose metabolism.

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Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

Cited by 89 publications

References 66 publications

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

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

WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

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