Similar Datasets
Project description:Estrogen-related receptors (ERR) α and γ were shown recently to serve as regulators of cardiac maturation, yet the underlying mechanisms have not been delineated. Herein, we find that ERR signaling is necessary for induction of genes involved in mitochondrial and cardiac-specific contractile processes during human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) differentiation. Genomic interrogation studies demonstrate that ERRγ occupies many cardiomyocyte enhancers/super-enhancers, often co-localizing with the cardiogenic factor GATA4. ERRγ interacts with GATA4 to cooperatively activate transcription of targets involved in cardiomyocyte-specific processes such as contractile function, whereas ERRγ-mediated control of metabolic genes occurs independent of GATA4. Both mechanisms require the transcriptional coregulator PGC-1α. A disease-causing GATA4 mutation is shown to diminish PGC-1α/ERR/GATA4 cooperativity and expression of ERR target genes are downregulated in human heart failure samples suggesting that dysregulation of this circuitry may contribute to congenital and acquired forms of heart failure.
| S-EPMC9008061 | biostudies-literature
Project description:The Nuclear Receptor ERR Cooperates with the Cardiogenic Factor GATA4 to Orchestrate Transcriptional Control of Cardiac Maturation
| PRJNA699166 | ENA
Project description:BackgroundFibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown.ResultsActivation of the hepatic CB1 receptor by arachidonyl-2'-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) ? increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERR? decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERR?, but not ERR? and ERR?, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERR?-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERR? to the FGF21 gene promoter. Finally, GSK5182, an ERR? inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion.ConclusionBased on our data, we conclude that ERR? plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion.
| S-EPMC4959684 | biostudies-literature
Project description:Determination of the genes regulated by ERRalpha nuclear receptor in MDA-MB231 cells MDA-MB231 cells were inactivated for ERRalpha using siRNA. Three different siRNAs were used (siE1, siE2, siE3). Cells treated with a control siRNA (siC samples) were used for comparison. Duplicate samples were analyzed. Transcriptomic analysis was performed by RNA-Seq
2014-09-17 | E-GEOD-49110 | biostudies-arrayexpress
Project description:Determination of the genes regulated by ERRalpha nuclear receptor in MDA-MB231 cells
2014-09-17 | GSE49110 | GEO
Project description:BackgroundPGC-1? is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERR? and ERR?) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1? and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1? binds in a strikingly different manner to ERR? ligand-binding domains (LBDs) compared to its mode of binding to ERR? and other nuclear receptors (NRs), where it interacts directly with the two ERR? homodimer subunits.Methods/principal findingsHere, we show that PGC-1? receptor interacting domain (RID) binds in an almost identical manner to ERR? and ERR? homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1? RID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions. NMR studies further defined the limits of PGC-1? RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1?/ERR? LBDs and PGC-1?/ERR? LBDs complexes share an identical architecture with an asymmetric binding of PGC-1? to homodimeric ERR.Conclusions/significanceThese studies provide the molecular determinants for the specificity of interactions between PGC-1? and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Our work indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators to homodimers.
| S-EPMC3706463 | biostudies-literature
Project description:PurposeTriple-negative breast cancer (TNBC)/basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer. We previously reported that a small molecule agonist ligand for the orphan nuclear receptor estrogen-related receptor beta (ERR? or ESRRB) has growth inhibitory and anti-mitotic activity in TNBC cell lines. In this study, we evaluate the association of ESRRB mRNA, copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens.MethodsESRRB mRNA-level expression and clinical associations were analyzed using RNAseq data. Array-based comparative genomic hybridization determined ESRRB copy number in African-American and Caucasian women. Transcription factor activity was measured using promoter-reporter luciferase assays in TNBC cell lines. Semi-automatic quantification of immunohistochemistry measured ERR? protein expression on a 150-patient tissue microarray series.ResultsESRRB mRNA expression is significantly lower in TNBC/BLBC versus other breast cancer subtypes. There is no evidence of ESRRB copy number loss. ESRRB mRNA expression is correlated with the expression of genes associated with neuroactive ligand-receptor interaction, metabolic pathways, and deafness. These genes contain G/C-rich transcription factor binding motifs. The ESRRB message is alternatively spliced into three isoforms, which we show have different transcription factor activity in basal-like versus other TNBC cell lines. We further show that the ERR?2 and ERR?sf isoforms are broadly expressed in breast tumors at the protein level.ConclusionsDecreased ESRRB mRNA expression and distinct patterns of ERR? isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.
| S-EPMC7153462 | biostudies-literature
Project description:GATA4-6 transcription factors regulate numerous aspects of development and homeostasis in multiple tissues of mesodermal and endodermal origin. In the heart, the best studied of these factors, GATA4, has multiple distinct roles in cardiac specification, differentiation, morphogenesis, hypertrophy and survival. To improve understanding of how GATA4 achieves its numerous roles in the heart, here we have focused on the carboxy-terminal domain and the residues required for interaction with cofactors FOG2 and Tbx5. We present evidence that the carboxy terminal region composed of amino acids 362-400 is essential for mediating cardiogenesis in Xenopus pluripotent explants and embryos. In contrast, the same region is not required for endoderm-inducing activity of GATA4. Further evidence is presented that the carboxy terminal cardiogenic region of GATA4 does not operate as a generic transcriptional activator. Potential mechanism of action of the carboxy terminal end of GATA4 is provided by the results showing physical and functional interaction with CDK4, including the enhancement of cardiogenic activity of GATA4 by CDK4. These results establish CDK4 as a GATA4 partner in cardiogenesis. The interactions of GATA4 with its other well described cofactors Tbx5 and FOG2 are known to be involved in heart morphogenesis, but their requirement for cardiac differentiation is unknown. We report that the mutations that disrupt interactions of GATA4 with Tbx5 and FOG2, G295S and V217G, respectively, do not impair cardiogenic activity of GATA4. These findings add support to the view that distinct roles of GATA4 in the heart are mediated by different determinants of the protein. Finally, we show that the rat GATA4 likely induces cardiogenesis cell autonomously or directly as it does not require activity of endodermal transcription factor Sox17, a GATA4 target gene that induces cardiogenesis non-cell autonomously.
| S-EPMC4259525 | biostudies-literature
Project description:Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERR?) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERR? specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERR?, whereas knockdown of ERR? attenuated fibrinogen expression. Deletion analyses of the fibrinogen ? (FGG) gene promoter and ChIP assays revealed binding sites of ERR? on human fibrinogen ? gene promoter. Moreover, overexpression of ERR? was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERR? led to its attenuation in cell culture. Finally, fibrinogen and ERR? gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERR? expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.
| S-EPMC5531639 | biostudies-literature
Project description:Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.
| S-EPMC8072258 | biostudies-literature