Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

Lam, Michael T.; Cho, Han; Lesch, Hanna P.; Gosselin, David; Heinz, Sven; Tanaka-Oishi, Yumiko; Benner, Chris; Kaikkonen, Minna U.; Kim, Aneeza S.; Kosaka, Mika; Lee, Cindy Y.; Watt, Andy; Grossman, Tamar R.; Rosenfeld, Michael G.; Evans, Ronald M.; Glass, Christopher K.

doi:10.1038/nature12209

Cited by 483 publications

(551 citation statements)

References 30 publications

(45 reference statements)

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“…This is consistent with previous findings that Rev-erb␣ is not transcriptionally active at all of its cistromic binding sites in the liver (44,48). The Rev-erb␣ dependence of eRNA transcription in WAT but not in other tissues may not only reflect the activity of the Klb enhancers but could also be playing a direct role in transcriptional regulation, as reported in macrophages (57).…”

Section: Discussionsupporting

confidence: 81%

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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Section: Discussionsupporting

confidence: 81%

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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“…S3F). Collectively, our data show the mechanism by which KLK3e forms a functional complex with AR and Med1 to promote transcription, supporting the findings that transfer of full enhancer activity to a target promoter depends on enhancer-bound transcription factors and enhancerderived RNA transcripts (14).…”

Section: Significancesupporting

confidence: 66%

“…The activity of eRNAs was shown to augment the expression of not only neighboring but also intrachromosomally distant genes to convey enhancer-dependent transcription (12,13). Recently, the 5′-GRO-seq data have revealed that sequencespecific transcription factors and eRNA transcripts are required for transfer of full enhancer activity to a target promoter (14). Moreover, eRNAs have been shown to configure a chromatin state that facilitate transcription factors binding on the target promoters at defined genomic loci (15).…”

Section: Klk3e/ar/med1 Complex | Chromosomal Loopingmentioning

confidence: 99%

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation

Hsieh

Teng

Chen

et al. 2014

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

329

364

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The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a wellknown AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R 2 = 0.6213, P < 5 × 10 −11 ) and KLK2 (R 2 = 0.5893, P < 5 × 10 −10 ) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.KLK3e/AR/Med1 complex | chromosomal looping

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“…Some enhancer-like RNAs were reported to interact with mediators and change the chromatin conformation to activate the target genes (60). eRNAs have been reported to establish the chromatin looping and generate the interaction of the enhancers with their target genes (61)(62)(63). In the current study, the lncPrep+96kb knockdown did not change the histone acetylation pattern in the Hepa1-6 cell (Fig.…”

Section: Discussionmentioning

confidence: 53%

A long non-coding RNA transcribed from conserved non-coding sequences contributes to the mouse prolyl oligopeptidase gene activation

Matsubara

Kurihara

Kimura

2013

The Journal of Biochemistry

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Note: Nucleotide sequence data for two types (2.2 kb and 2.8 kb) of lncPrep+96kb reported in this paper are available in the DDBJ/EMBL/GenBank databases under the accession numbers AB849012 and AB849013, respectively. SummaryProlyl oligopeptidase (POP) is a multifunctional protease which is involved in many physiological events, but its gene regulatory mechanism is poorly understood. To identify novel regulatory elements of the POP gene, we compared the genomic sequences at the mouse and human POP loci and found six conserved noncoding sequences (CNSs) at adjacent intergenic regions. From these CNSs, four long noncoding RNAs (lncRNAs) were transcribed and the expression pattern of one (lncPrep+96kb) was correlated with that of POP. lncPrep+96kb was transcribed as two forms due to the different transcriptional start sites and was localized at the nucleus and cytoplasm, although more was present at the nucleus. When we knocked down lncPrep+96kb in the primary ovarian granulosa cell and a hepatic cell line, the POP expression was decreased in both cells. In contrast, overexpression of lncPrep+96kb increased the POP expression only in the granulosa cell. Because lncPrep+96kb was upregulated with the same timing as POP in the hormone-treated ovary, this lncRNA could play a role in the POP gene activation in the granulosa cell.Moreover, a downstream region of the human POP gene was also transcribed. We propose a novel mechanism for the POP gene activation.Keywords: prolyl oligopeptidase/ long noncoding RNA/ conserved noncoding sequence/ granulosa cell/ skeletal muscle 4

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Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

Cited by 483 publications

References 30 publications

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

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

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation

A long non-coding RNA transcribed from conserved non-coding sequences contributes to the mouse prolyl oligopeptidase gene activation

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