Deoxyribonucleic Acid Response Element-Dependent Regulation of Transcription by Orphan Nuclear Receptor Estrogen Receptor-Related Receptor γ

Sanyal, Sabyasachi; Matthews, Jason; Bouton, Didier; Kim, Han Jong; Choi, Hueng Sik; Treuter, Eckardt; Gustafsson, Jan Åke

doi:10.1210/me.2003-0165

Cited by 42 publications

(27 citation statements)

References 58 publications

(111 reference statements)

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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%

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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%

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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“…Whether PGC-1 enhances or stabilizes binding of the ERR to MHRE is not clear; it is known that the receptor conformation can be modified and its activity modulated upon binding to the response element and by interaction with the coactivators (Klinge et al 2001, Loven et al 2001, Wood et al 2001, Hall et al 2002, Sanyal et al 2002. ERR exhibits different coactivator recruitments and transcriptional activity, depending on the response element (Sanyal et al 2004). Binding of ERR to the MHRE could change its conformation and increase interaction with PGC-1 , thus forming a strong activation complex.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

Liu¹,

Zhang²,

Teng³

2005

Journal of Molecular Endocrinology

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The expression of estrogen-related receptor-(ERR ) is stimulated by estrogen in selective tissues. Recently, a correlation between ERR expression and the induction of peroxisome proliferator-activated receptor-coactivator-1 (PGC-1 ) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERR regulation by diverse signals, the promoter of the human ERR gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERR gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERR bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1 in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERR by small interfering RNA, and increasing the ERR level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1 . The activation function 2 domain of the ERR and the L2 and L3 motifs of PGC-1 were essential to transactivate the MHRE. Additionally, PGC-1 increases the amount of endogenous ERR bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERR gene is a target for ERR transactivation, which is enhanced by PGC-1 .

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“…Total DNA amounts in all cases were kept to a constant by using empty pcDNA3 vectors. Luciferase assays were performed as described elsewhere (37).…”

Section: Methodsmentioning

confidence: 99%

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Sanyal

Båvner

Haroniti

et al. 2007

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

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Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1-and HNF4␣-dependent expression of cholesterol 7␣ hydroxylase (CYP7A1) and sterol 12␣ hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4␣, and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders.cholesterol 7␣ hydroxylase ͉ sterol 12␣ hydroxylase ͉ farnesoid X receptor ͉ small heterodimer partner B ile acids (BAs) are cholesterol derivatives essential for absorption of dietary lipids and fat-soluble vitamins and maintenance of cholesterol BA homeostasis (1, 2). In humans the major BA biosynthetic pathway is initiated by cholesterol 7␣ hydroxylase (CYP7A1) to produce two primary BAs, cholic acid and chenodeoxycholic acid (CDCA). Sterol 12␣ hydroxylase (CYP8B1) catalyzes the synthesis of cholic acid and determines the ratio of cholic acid to CDCA in the bile (1). In addition to emulsification of dietary lipids, cholic acid and CDCA are ligands for farnesoid X receptor (FXR/NR1H4) (3-5). Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7-10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12, 13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14). Although the physiological role of SHP in BA biosynthesis is well documented, mechanistic details of repression by SHP remain unclear. Recent studies indicate that SHP may repress its targets (i) via direct binding and blocking the coactivator interaction interface of its target nuclear receptors (NRs), (ii) by antagonizing CREB binding protein (CBP)/p300-dependent coactivator functions on NRs via recruitment of a coinhibitor protein like EID1, and (iii) by recruiting corepressor complexes that include histone deacetylases (HDAC) 1, 3, and 6, Sin3A...

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Deoxyribonucleic Acid Response Element-Dependent Regulation of Transcription by Orphan Nuclear Receptor Estrogen Receptor-Related Receptor γ

Cited by 42 publications

References 58 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

Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

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