A Single Nucleotide in an Estrogen-Related Receptor α Site Can Dictate Mode of Binding and Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activation of Target Promoters

Barry, Janelle B.; Laganière, Josée; Giguère, Vincent

doi:10.1210/me.2005-0313

Cited by 47 publications

(40 citation statements)

References 39 publications

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“…There are also no obvious ERR consensus sites within the HIF2α promoter sequence and PGC-1α does not directly coactivate HIF2α (Fig. S3) (49). Further studies of the upstream events that regulate HIF2α expression through PGC-1α are warranted and could lead to new therapeutic targets affecting fiber-type determination.…”

Section: Discussionmentioning

confidence: 99%

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Rasbach

Gupta

Ruas

et al. 2010

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

127

105

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The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1α has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1α in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 α (HIF2α) as a major PGC-1α target in skeletal muscle that is positively regulated by both exercise and β-adrenergic signaling. This transcriptional regulation of HIF2α is completely dependent on the PGC-1α/ERRα complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2α target genes in primary myotubes suggested an unexpected role for HIF2α in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1α–mediated switch to slow, oxidative fibers in vitro is dependent on HIF2α, and mice with a muscle-specific knockout of HIF2α increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise.

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Section: Discussionmentioning

confidence: 99%

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Rasbach

Gupta

Ruas

et al. 2010

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

127

105

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“…Nonetheless, ERRγ has been reported to bind a broad range of sequences, including the monovalent binding sites (Razzaque et al, 2004), whereas ERRα also binds variety of response sequences (Barry et al, 2006;Johnston et al, 1997) including the NRRE-1 of the medium chain acyl-coenzyme A dehydrogenase (MCAD) gene at sites with 14 bases in the middle (Maehara et al, 2003). Recently, Giguere's laboratory demonstrated that a single nucleotide change in ERRα binding site can affect the mode of PGC-1α activation of its target promoters (Barry et al, 2006). Thus, the binding characteristics of ERRs may influence the recruitment of coactivators and the transactivation activity.…”

Section: Discussionmentioning

confidence: 99%

Interplay between estrogen-related receptor alpha (ERRα) and gamma (ERRγ) on the regulation of ERRα gene expression

Zhang

Teng

2007

Molecular and Cellular Endocrinology

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Estrogen-related receptor α (ERRα) modulates estrogen receptor (ER)-mediated activity and is participating in the energy homeostasis by regulation of downstream target genes. The ERRα gene itself is proposed to be regulated by peroxisome proliferator-activated receptor γ coactivator (PGC-1α) through an autoregulatory loop under physiological stimulation. We have previously shown that the close family member ERRγ is a positive regulator of ERRα gene expression. ERRα and ERRγ are coexpressed in metabolically active tissues such as heart, kidney and muscle, yet the physiological role of ERRγ and its relationship with ERRα in gene regulation are currently unknown. The present study examined the interplay of ERRγ and ERRα in regulation of ERRα gene expression. Using real-time PCR analyses we found that ERRγ, like the ERRα and PGC-1α is induced in mouse liver during fasting. Overexpression of ERRγ in the HEC-1B cells robustly stimulated the multihormone response element (MHRE) of the ERRα gene promoter and this activity was repressed by increasing expression of ERRα. The two ERRs bind MHRE simultaneously in electrophoretic mobility shift assay (EMSA) and they were detected as multimeric complexes in cells by coimmunoprecipitation. Although ERRα and ERRγ share high sequence identity, they differ in biochemical and molecular characteristics as examined by trypsin digestion, reporter activation, and coactivator interaction and utilization. Using chromatin immunoprecipitation (ChIP) assay, we showed that ectopic expression of both ERRα and ERRγ modifies chromatin structure at the MHRE region while ectopic expression of PGC-1α in HEC-1B cells promotes ERRγ but not ERRα occupancy at the MHRE region of the ERRα gene promoter and enhances the recruitment of coactivator SRC1. These data suggested that ERRα and ERRγ regulate ERRα gene expression with different molecular mechanisms.

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“…ERR␣ dimers are capable of binding to either EREs or ERREs with a slight preference for an A or a T at the ϩ2 position in the latter, whereas a C at the ϩ2 position, as found in the ERRE located in P2, would favor monomer binding (51). In this and previous studies Giguere and coworkers (51,52) demonstrated that the coactivator PGC-1 interacts with dimers of DNA-bound ERR␣, but not mono- mers, and given the ability of PGC-1␣ to potentiate ERR␣ stimulation of the P2 promoter, it is conceivable that this is achieved by dimeric ERR␣ binding to the ERE.…”

Section: Discussionmentioning

confidence: 99%

RIP140 Expression Is Stimulated by Estrogen-related Receptor α during Adipogenesis

Nichol

Christian

Steel

et al. 2006

Journal of Biological Chemistry

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RIP140 is a corepressor for nuclear receptors that regulates energy expenditure in adipose tissue by suppressing the expression of clusters of metabolic genes involved in glucose and lipid metabolism. The gene encoding RIP140/Nrip1 contains only one coding exon but has multiple promoters and 5 non-coding exons that are subject to alternative splicing. In adipocytes we have defined a promoter, referred to as P2, that is preferentially utilized and activated during adipogenesis. Expression studies and chromatin immunoprecipitation experiments indicate that estrogen-related receptor ␣ (ERR␣), the level of which increases during adipogenesis in parallel with RIP140, stimulates transcription from the P2 promoter. Further analysis indicates that ERR␣ is capable of activating RIP140 gene transcription by two mechanisms, directly by binding to an estrogen receptor element/ERR element at ؊650/؊633 and indirectly through Sp1 binding sites in the proximal promoter. Thus, the up-regulation of RIP140 by ERR␣ during adipogenesis may provide an inhibitory feedback mechanism to control the expression of many nuclear receptor target genes.Adipogenesis is regulated by the coordinated expression of transcription factors that control the formation and function of white adipose tissue as a fat storage depot. The identification of many of these transcription factors has relied upon the analysis of preadipocyte cell lines, notably 3T3-L1, that can be induced to undergo differentiation upon exposure to a number of hormone signals, namely glucocorticoid, insulin, and inducers of cAMP. This leads to the activation of a cascade of transcription factors including CCAAT enhancer-binding protein ␤, CCAAT enhancer-binding protein ␦, and SREBP1c that then induce the expression of peroxisome proliferator-activated receptor ␥ and CCAAT enhancer-binding protein ␣ and the formation of adipocytes (1-5). Many other transcription factors, such as Krupple-like factor 5 and E2F1, also facilitate adipogenesis by promoting expression of peroxisome proliferatoractivated receptor ␥, whereas some, such as E2F4 and GATA2/3 that are inhibitory, are down-regulated during adipogenesis (6 -9). The importance of these transcription factors has been confirmed by the analysis of mouse gene knockouts, but CCAAT enhancer-binding protein ␣ and peroxisome proliferator-activated receptor ␥2 appear to play a crucial role, with the latter often regarded as a master regulator of adipogenesis (10 -12).The function of adipose tissue in the control of fat storage and utilization also depends on the transcriptional control of networks of genes. Among the many transcription factors that control metabolic gene networks are nuclear receptors including peroxisome proliferator-activated receptors, thyroid hormone receptors, and estrogen-related receptors (ERRs) 2 (11-17). The ability of nuclear receptors to regulate the expression of genes involved in triglyceride synthesis or fatty acid oxidation is mediated by coactivators and corepressors. Among these are the PGC-1 coactivators ...

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A Single Nucleotide in an Estrogen-Related Receptor α Site Can Dictate Mode of Binding and Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activation of Target Promoters

Cited by 47 publications

References 39 publications

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Interplay between estrogen-related receptor alpha (ERRα) and gamma (ERRγ) on the regulation of ERRα gene expression

RIP140 Expression Is Stimulated by Estrogen-related Receptor α during Adipogenesis

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