Estrogen receptor-related receptor γ has an exceptionally broad specificity of DNA sequence recognition

Razzaque, Abdur; Masuda, Nobuyuki; Maeda, Yusaku; Endo, Yaeta; Tsukamoto, Tomoko; Osumi, Takashi

doi:10.1016/j.gene.2004.07.010

Cited by 50 publications

(45 citation statements)

References 30 publications

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“…Recent findings of several laboratories demonstrate that the sequence of DNA binding element is important in regulating the ERRγ transactivation function (Razzaque et al, 2004;Sanyal et al, 2004). Consistent with these reports, we found that the AAB of the ERRα gene and the synthetic 3x ERE which contain multiple ERE half sites, are very sensitive to ERRγ stimulation whereas 1x ERE and the NRRE of the MCAD gene are less responsive (Fig 6A).…”

Section: Differential Molecular Characteristics Of the Errα And Errγsupporting

confidence: 91%

“…It is known that ERRγ is a strong activator of selective response elements (Razzaque et al, 2004;Sanyal et al, 2004), interacts with PGC-1α Huss et al, 2002) and stimulates the ERRα gene promoter via the MHRE (Liu et al, 2005). Furthermore, treatment of HEC-1B cells with ERRγ siRNA significantly reduced the ERRα mRNA expression (Liu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…6B) and the changes of conformation could lead to the recruitment of coactivators or release of corepressors, thus affecting its transactivation function. The biological implication of ERRγ conformational change upon binding to different response elements is not clear but may be important to its functional roles, especially since it has a broad range of binding specificity (Razzaque et al, 2004). Another major difference between ERRα and ERRγ is that ERRγ interacts strongly with SRC1, a coactivator not only required for the transactivation function of nuclear receptors but also needed to increase the potency of PGC-1α (Puigserver et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…It is unusual for a nuclear receptor to bind two ERE half site with such wide space in between. 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).…”

Section: Discussionmentioning

confidence: 99%

“…However, on the 1x ERE, regardless of the weak binding, ERRγ formed a heterodimer with the ERRα. ERα did not heterodimerize with ERRα (Zhang and Teng, 2000;Zhang and Teng, 2001) or ERRγ (Razzaque et al, 2004) and served as a control (Fig. 4C).…”

Section: Functional and Physical Interaction Of Errα And Errγ On The mentioning

confidence: 99%

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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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Section: Differential Molecular Characteristics Of the Errα And Errγsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Functional and Physical Interaction Of Errα And Errγ On The mentioning

confidence: 99%

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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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α‐Helix‐peptides comprising the human nuclear receptor ERRγ competitively provoke inhibition of functional homomeric dimerization

et al. 2016

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Estrogen-related receptor γ (ERRγ) is a constitutively active nuclear receptor functioning as a transcription factor. ERRγ binds to a single half site designated as ERRE that has only a single DNA-binding motif. However, with regard to the subunit structure, it remains a matter of controversy whether ERRγ binds as a monomer or dimer. Because the ligand-binding domain (LBD) of ERRγ was in a homodimer form in its X-ray crystal structure, the peptide fragments present in the dimer interfaces would perturb or destabilize the dimer structure by inhibiting the mutual interaction among ERRγ molecules. Thus, to demonstrate the essential homodimer structure of ERRγ, we utilized the peptides corresponding to the α-helix peptides 7 (H7), H9, and H10/11 in order to test such inhibitor activity. These selections were done based on a structural analysis of the X-ray crystal structures of ERRγ-LBD, which forms a head-to-head dimer structure. Peptides were evaluated by means of a luciferase reporter gene assay, in which ERRγ exhibited a high constitutive activity with no ligand. When the peptide was expressed in the HeLa cells together with ERRγ, these peptides clearly showed a concentration-dependent activity inhibition, indicating that ERRγ is indeed homodimerized as required for DNA transcription activity. The present results strongly suggest that human nuclear receptor ERRγ functions as a genuine homomeric dimer with symmetrical dimeric interface regions. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 547-554, 2016.

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Divergent regulation of theOsteopontinpromoter by the estrogen receptor-related receptors is isoform- and cell context dependent

2013

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We sought to determine whether the estrogen receptor-related receptor gamma (mEsrrg) regulated the Osteopontin (Opn) promoter through the same AP1/CAAT box element that we have previously described for mEsrra. In HeLa cells mEsrrg used an additional site present in the 5'UTR, while in ROS17/2.8 cells the AP1/CAAT site was not used, but a completely novel site surrounding the transcription start site was used. We also find that in ROS17/2.8 cells mEsrra repressed, while mEsrrg activated the Opn promoter. None of the sites identified conform to established Esrr response elements (ERREs). Additionally, the two reported mEsrrg protein isoforms showed differences in their activation potential. Mutations in the activation function 2 (AF2) of mEsrra, predicted to abolish activation, surprisingly turned mEsrra into a better activator. In contrast, similar AF2 mutations in Esrrg2 abolished its ability to activate the Opn promoter. Mutation of the DNA binding domain of mEsrra/g2 abolished transcriptional activity in HeLa and ROS17/2.8 cells. Our data indicate, first, that the two Esrr isoforms regulate Opn in a cell context-dependent manner. Second, they suggest that although the DNA binding domains of mEsrra and mEsrrg are 93% identical and required for regulation, the receptors bind to distinct Opn promoter elements, suggesting that the two isoforms may co-regulate Opn, and perhaps other genes, without competing for the same site in the promoter. Finally, the results suggest that each isoform interacts differently with co-activators and co-repressors, as highlighted by the AF2 mutation that turns mEsrra into a better activator but abolishes activity of Esrrg2.

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Estrogen receptor-related receptor γ has an exceptionally broad specificity of DNA sequence recognition

Cited by 50 publications

References 30 publications

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

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

α‐Helix‐peptides comprising the human nuclear receptor ERRγ competitively provoke inhibition of functional homomeric dimerization

Divergent regulation of theOsteopontinpromoter by the estrogen receptor-related receptors is isoform- and cell context dependent

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