{"gene":"ESRRG","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"BPA binds to the ERRγ ligand-binding domain (LBD) with high affinity (KD = 5.5 nM). Crystal structure of the ERRγ-LBD/BPA complex revealed that BPA is anchored by hydrogen bonds between its two phenol-hydroxyl groups and residues Glu275, Arg316, and Asn346, with additional hydrophobic contacts especially with Tyr326. BPA binding preserves the active conformation of helix 12, thereby maintaining ERRγ constitutive transcriptional activity. ERRγ behaves as a constitutive activator of transcription in the absence of a known endogenous ligand.","method":"X-ray crystallography of ERRγ-LBD/BPA complex; prior biochemical binding assay (KD determination)","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with atomic resolution of ligand-receptor interaction, combined with prior biochemical binding assay; mechanistically rigorous single study","pmids":["17761695"],"is_preprint":false},{"year":2009,"finding":"An ERRγ isoform (type-1) bearing an additional 23-mer amino-acid sequence at the N-terminus elevates ERRγ basal constitutive transcriptional activity by approximately 50%, as demonstrated by luciferase reporter gene assay. Placenta exclusively expresses this type-1 isoform among ERRγ protein isoforms.","method":"Luciferase reporter gene assay; real-time PCR; identification of ERRγ mRNA variants and protein isoforms in human reproductive tissues","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay demonstrating isoform-specific activity difference; single lab, single study","pmids":["19304792"],"is_preprint":false},{"year":2010,"finding":"Esrrg protein is detected in early ureteric ducts (cytoplasmic/sub-membranous) and in developing nephrons (nuclear localization). siRNA-mediated knockdown and small-molecule agonist-induced aberrant activation of Esrrg in embryonic mouse kidney cultures both caused severe abnormality of early branching events of the ureteric duct. Esrrg homozygous knockout mice (Esrrg−/−) displayed agenesis of the renal papilla with otherwise normal cortex and medulla development, establishing Esrrg as required for ureteric bud branching prior to nephrogenesis onset.","method":"Immunostaining for subcellular localization; siRNA knockdown in embryonic kidney explant culture; small-molecule agonist treatment; targeted gene knockout mouse model (Esrrg−/−)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (siRNA, pharmacological, genetic KO) with defined morphological phenotype; in vivo validation","pmids":["21138943"],"is_preprint":false},{"year":2021,"finding":"ERRγ expression is induced in the liver during acute kidney injury (AKI) by upstream IL-6 signaling. Hepatic ERRγ overexpression is sufficient to induce hepatic FGF23 production. Liver-specific depletion of ERRγ or treatment with an inverse ERRγ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in folic acid-induced AKI mice. IL-6 neutralizing antibody reduced ERRγ-mediated FGF23 production, confirming the IL-6 → ERRγ → FGF23 axis.","method":"Ectopic overexpression; liver-specific genetic depletion; inverse agonist pharmacological inhibition; IL-6 neutralizing antibody; folic acid-induced AKI mouse model; plasma FGF23 measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic overexpression, liver-specific KO, pharmacological inhibitor, antibody neutralization) in vivo, with defined molecular pathway placement","pmids":["33853949"],"is_preprint":false},{"year":2021,"finding":"Esrrg controls regulatory T cell (Treg) maintenance and function through mitochondrial homeostasis. Esrrg-deficient Tregs exhibit dysregulated mitochondria with decreased oxygen consumption, ATP production, and NAD+ levels. Esrrg deficiency also leads to decreased phosphatidylinositol and TGF-β signaling and increased mTOR complex 1 activation in Tregs, impaired differentiation into follicular Tregs, and enhanced follicular helper T cell responses, resulting in global T cell activation and autoimmunity in aged mice.","method":"Conditional knockout mouse model; mitochondrial oxygen consumption assay; ATP and NAD+ quantification; phospho-signaling pathway analysis; T cell subset phenotyping; ESRRG knockdown in Jurkat cells with metabolic readout","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal metabolic and immunological readouts; in vivo autoimmunity phenotype and in vitro metabolic validation","pmids":["34156979"],"is_preprint":false},{"year":2022,"finding":"RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation in retinoblastoma cells. ESRRG regulates genes involved in retinogenesis and oxygen metabolism and is preferentially expressed in hypoxic retinoblastoma cells in vivo. Depletion or inhibition of ESRRG causes marked retinoblastoma cell death, which is exacerbated under hypoxia.","method":"Protein interaction assay (RB1-ESRRG direct interaction); whole exome/transcriptome/single-cell transcriptome genomic analyses; ESRRG depletion/inhibition with cell death readout; in vivo tumor hypoxia expression analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction and functional depletion with defined phenotype; single lab study, abstract does not fully detail interaction method rigor","pmids":["35984874"],"is_preprint":false},{"year":2020,"finding":"Sophoridine promotes β-catenin degradation by enhancing ESRRG expression in gastric cancer cells, independently of ubiquitination-proteasome pathway, TRIM33-mediated GSK3β-independent pathway, or altered GSK3β activity. ESRRG-mediated β-catenin degradation underlies the tumor-suppressive effects of sophoridine.","method":"siRNA transfection; nuclear/cytoplasmic fractionation; western blot; CCK-8, EDU, colony forming, transwell, and flow cytometry assays in AGS and SGC7901 cells","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with siRNA and fractionation, multiple cell-based functional assays; single lab","pmids":["32571331"],"is_preprint":false},{"year":2020,"finding":"ESRRG and PERM1 are involved in the PGC1α transcriptional network to positively regulate mitochondrial capacity in adipocytes. Increased expression of ESRRG supports the formation of brown or brite/beige adipocytes both in vitro and in vivo, indicating ESRRG is an early inducer and important regulator of brite/beige adipocyte formation and mitochondrial conversion.","method":"Transcriptome profiling of inguinal adipocytes during cold exposure; in vitro and in vivo overexpression experiments; functional measurement of mitochondrial uncoupled respiration","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro overexpression with functional mitochondrial readout; transcriptome supporting data; single lab","pmids":["32595605"],"is_preprint":false},{"year":2016,"finding":"ERRγ overexpression attenuates puromycin aminonucleoside (PAN)-induced podocyte apoptosis and stimulates PI3K/Akt signaling (increased expression of PI3K subunits p85α and p110α and phosphorylated Akt). Conversely, ERRγ siRNA silencing causes podocyte apoptosis with increased injury markers (B7-1, cathepsin L) and decreased nephrin. A specific PI3K inhibitor (LY294002) entirely reversed the anti-apoptotic effect of ERRγ, establishing PI3K/Akt as the downstream effector pathway.","method":"siRNA knockdown; overexpression; PI3K inhibitor rescue experiment; western blot for signaling pathway components; apoptosis assay; in vivo PAN-treated rat kidney model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue to establish pathway; single lab","pmids":["27417234"],"is_preprint":false},{"year":2023,"finding":"ESRRG directly interacts with the PKM2 promoter to inhibit its transcriptional activity in esophageal squamous cell carcinoma (ESCC) cells, thereby suppressing glycolysis (Warburg effect). The ESRRG-specific agonist DY131 inhibits ESCC cell proliferation and glycolysis by modulating glycolysis pathway genes, and also modulates lactate regulation relevant to immune checkpoint activity.","method":"Promoter luciferase assay; altered ESRRG expression in ESCC cell lines; metabolic assays for glycolysis; DY131 agonist treatment; bioinformatics analysis","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and functional metabolic readout; single lab, abstract-level detail on methods","pmids":["37679788"],"is_preprint":false},{"year":2022,"finding":"BPA affects the ESRRG signaling pathway in a sex-specific manner in human placentas: BPA (1 µM, 24 h) increased ESRRG mRNA and protein in female placentas but decreased them in male placentas (at 1 nM or 1 µM, 48 h). Downstream ESRRG targets HSD17B1 and PLAC1 were correspondingly altered in a sex-specific pattern. BPA treatment did not affect proliferation, apoptosis, or syncytiotrophoblast differentiation.","method":"Placental villous explant culture with BPA; mRNA and protein quantification; sex-stratified analysis of ESRRG pathway constituents","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo human tissue explant with mRNA and protein quantification at multiple doses and timepoints; single lab, sex-stratified analysis","pmids":["35220427"],"is_preprint":false},{"year":2024,"finding":"ESRRG functions as a transcription factor that directly binds the Kcnn1 (KCNN1) gene promoter in dorsal root ganglion (DRG) neurons. Peripheral nerve injury reduces DRG ESRRG expression, leading to reduced KCNN1 transcription. This downregulation decreases total potassium voltage currents and afterhyperpolarization currents, increasing neuronal excitability and nociceptive hypersensitivity. Rescuing KCNN1 expression prevented CCI-induced pain behaviors without affecting locomotion or acute pain.","method":"Chromatin immunoprecipitation (ChIP) assay demonstrating ESRRG binding to Kcnn1 promoter; siRNA-mediated knockdown; AAV-mediated rescue; electrophysiology (potassium current and AHP measurement); behavioral pain assays in CCI and L4 ligation mouse models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding by ChIP, electrophysiological validation, in vivo genetic rescue with defined molecular and behavioral phenotype; multiple orthogonal methods in single rigorous study","pmids":["38912580"],"is_preprint":false},{"year":2025,"finding":"ESRRG binds to the Pde3b (phosphodiesterase 3B) promoter, as demonstrated by dual luciferase reporter assay and chromatin immunoprecipitation PCR. Esrrg inhibition (by AAV-shEsrrg or inverse agonist GSK5182) reduces Pde3b expression and alleviates airway inflammation in PM2.5-aggravated asthmatic mice and in isolated mouse tracheobronchial epithelial cells.","method":"Dual luciferase reporter assay; chromatin immunoprecipitation PCR; AAV-mediated shRNA knockdown; pharmacological inverse agonist (GSK5182); in vivo asthma-PM2.5 mouse model; in vitro tracheobronchial epithelial cell model","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct promoter binding confirmed by ChIP and reporter assay, in vivo and in vitro functional validation; single lab but multiple orthogonal methods","pmids":["40153608"],"is_preprint":false},{"year":2025,"finding":"De novo heterozygous variants in ESRRG (located in DNA-binding and ligand-binding domains) reduce transcriptional activity at ERR response elements (ERRE) as assessed by reporter gene assay in ESRRG-knockout HEK293T cells. ESRRG knockout increases cell proliferation, and wild-type ESRRG overexpression restores normal proliferation, while the identified disease variants do not. All identified variants retain correct nuclear localization. These findings implicate ESRRG gain-of-function transcriptional activity in cell proliferation control.","method":"ERRE luciferase reporter gene assay in ESRRG-KO HEK293T cells (transient transfection of each variant vs. wild-type); cell proliferation assay; immunofluorescence for subcellular localization; molecular modeling","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and proliferation assay with multiple patient-derived variants in defined KO background; single lab, abstract-level method description","pmids":["41265451"],"is_preprint":false},{"year":2025,"finding":"ESRRG mediates HSD11B2 transcription; propofol suppresses ESRRG expression in hippocampal neurons of 3xTg-AD mice, thereby reducing HSD11B2 and causing mitochondrial dysfunction (decreased membrane potential, increased cytochrome C release, increased p-DRP1). ESRRG overexpression (AAV-mediated) mitigated propofol-induced mitochondrial dysfunction and postoperative cognitive dysfunction, but these effects were reversed by HSD11B2 knockdown, establishing ESRRG → HSD11B2 as a functional transcriptional axis.","method":"AAV-mediated ESRRG overexpression; HSD11B2 knockdown; in vivo behavioral testing (Morris water maze); mitochondrial function assays (MMP, ROS, cytochrome C, p-DRP1); in vitro HT22 neuronal cell experiments","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro genetic manipulation with mechanistic rescue experiment establishing transcriptional axis; single lab","pmids":["41197937"],"is_preprint":false},{"year":2026,"finding":"ESRRG is uniquely and highly expressed at the 2-cell embryo stage in mice and is essential for blastocyst formation. ESRRG knockdown reduces global transcriptional activity in 2-cell embryos, impairing zygotic genome activation (ZGA) and the 2-cell to 4-cell transition. The transcription factor TRPS1 directly binds to the Esrrg promoter to regulate its expression. The TRPS1-ESRRG axis controls ZGA factors including Sp1 and tankyrase 2.","method":"siRNA/morpholino knockdown of Esrrg in mouse preimplantation embryos; global transcriptional activity assay; ChIP or equivalent assay showing TRPS1 binding to Esrrg promoter; embryo developmental staging","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo embryo knockdown with transcriptional and developmental phenotype, upstream regulator identified; single lab, abstract-level method detail","pmids":["42248279"],"is_preprint":false},{"year":2009,"finding":"Esrrg expression is significantly upregulated (2.36-fold) by fenofibrate treatment in ApoA-I transgenic mice and shows significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating a role for ERRγ in mediating fenofibrate-induced activation of specific lipid metabolism target genes.","method":"Global gene expression profiling (microarray) in ApoA-I transgenic mice treated with fenofibrate; bioinformatics correlation analysis","journal":"The pharmacogenomics journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — correlational expression profiling only; no direct functional manipulation of ESRRG; single study","pmids":["19949424"],"is_preprint":false},{"year":2026,"finding":"ESRRG downregulation in trophoblasts impairs mitochondrial function (decreased ATP, abnormal mitochondrial morphology) and reduces proliferation, invasion, migration, and tube formation in HTR-8/SVneo cells. ESRRG overexpression in a lipopolysaccharide-induced abortion mouse model improved trophoblast functionality and increased the number of retained embryos in the uterus.","method":"CCK8 and Transwell assays; MitoSOX staining; JC-1 mitochondrial membrane potential assay; ATP quantification; transmission electron microscopy; in vivo mouse overexpression model","journal":"Annals of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mitochondrial and functional assays with in vivo validation; single lab","pmids":["41623023"],"is_preprint":false}],"current_model":"ESRRG (ERRγ) is an orphan nuclear receptor that functions as a constitutive transcriptional activator, binding to ERR response elements (ERREs) to regulate genes involved in mitochondrial metabolism, lipid homeostasis, steroidogenesis, and developmental programs; its LBD adopts an active conformation without a known endogenous ligand and is a high-affinity receptor for the endocrine disruptor BPA; it directly controls target gene transcription by binding promoters of KCNN1, PKM2, PDE3B, and HSD11B2, and is negatively regulated by direct interaction with RB1; it is required for ureteric bud branching morphogenesis, renal papilla formation, Treg mitochondrial homeostasis, zygotic genome activation, podocyte survival via PI3K/Akt signaling, and hepatic FGF23 production downstream of IL-6 in acute kidney injury."},"narrative":{"mechanistic_narrative":"ESRRG (ERRγ) is an orphan nuclear receptor that acts as a constitutive transcriptional activator at ERR response elements, coordinating mitochondrial metabolic programs, developmental transitions, and tissue-specific gene expression across multiple organ systems [PMID:17761695, PMID:41265451]. Its ligand-binding domain adopts an active conformation in the absence of a known endogenous ligand, and it serves as a high-affinity receptor for the endocrine disruptor bisphenol A (KD = 5.5 nM), which is anchored within the LBD by hydrogen bonds to Glu275, Arg316, and Asn346 and stabilizes the active helix-12 conformation [PMID:17761695]. ERRγ exerts its effects largely by directly binding target gene promoters: it represses the glycolytic gene PKM2 to suppress the Warburg effect in carcinoma cells [PMID:37679788], represses PDE3B in airway epithelium [PMID:40153608], and activates KCNN1 in sensory neurons to control potassium currents and nociceptive excitability [PMID:38912580] and HSD11B2 in hippocampal neurons to maintain mitochondrial integrity [PMID:41197937]. A recurrent theme across tissues is its control of mitochondrial homeostasis and oxidative capacity — in regulatory T cells, where loss disrupts respiration and ATP/NAD+ levels and provokes autoimmunity [PMID:34156979], in beige/brown adipocytes through the PGC1α network [PMID:32595605], and in trophoblasts [PMID:41623023]. ERRγ is required for ureteric bud branching and renal papilla formation [PMID:21138943], for zygotic genome activation in 2-cell embryos downstream of TRPS1 [PMID:42248279], and is induced in the liver by IL-6 to drive FGF23 production during acute kidney injury [PMID:33853949]. Its transcriptional activity is held in check by direct interaction with RB1 [PMID:35984874]. De novo heterozygous ESRRG variants in the DNA- and ligand-binding domains alter transcriptional activity and dysregulate cell proliferation, implicating the receptor in a human developmental disorder [PMID:41265451].","teleology":[{"year":2007,"claim":"Established the structural basis for ERRγ's constitutive activity and its capture by an environmental xenoestrogen, answering how a receptor without an endogenous ligand stays active and how BPA hijacks it.","evidence":"X-ray crystallography of the ERRγ-LBD/BPA complex plus biochemical binding (KD determination)","pmids":["17761695"],"confidence":"High","gaps":["No endogenous ligand identified","Does not address physiological consequences of BPA binding in tissues"]},{"year":2009,"claim":"Showed that N-terminal isoform variation tunes ERRγ's basal transcriptional output and that the placenta selectively expresses a higher-activity isoform, linking isoform choice to tissue-specific activity.","evidence":"Luciferase reporter assay and RT-PCR isoform mapping in human reproductive tissues","pmids":["19304792"],"confidence":"Medium","gaps":["Target genes affected by the activity difference not defined","Single-study reporter quantification"]},{"year":2010,"claim":"Defined ERRγ as an in vivo developmental regulator, demonstrating it is required for ureteric bud branching and renal papilla formation.","evidence":"siRNA, pharmacological agonist, and germline knockout in embryonic mouse kidney","pmids":["21138943"],"confidence":"High","gaps":["Direct transcriptional targets in branching morphogenesis not identified","Mechanism linking activity to branching unresolved"]},{"year":2016,"claim":"Connected ERRγ to podocyte survival, establishing PI3K/Akt as the effector pathway through which it protects against injury-induced apoptosis.","evidence":"Gain/loss-of-function with PI3K inhibitor rescue in podocytes and PAN rat model","pmids":["27417234"],"confidence":"Medium","gaps":["Direct transcriptional targets upstream of PI3K not identified","Single lab"]},{"year":2020,"claim":"Placed ERRγ within the PGC1α mitochondrial network as an early inducer of brite/beige adipocyte formation, and separately as a mediator of β-catenin degradation in gastric cancer.","evidence":"Adipocyte transcriptome profiling with in vitro/in vivo overexpression and mitochondrial respiration; siRNA and fractionation in gastric cancer cells","pmids":["32595605","32571331"],"confidence":"Medium","gaps":["Direct promoter targets in adipocytes not defined","Mechanism of ESRRG-driven β-catenin degradation not molecularly resolved"]},{"year":2021,"claim":"Demonstrated that ERRγ governs mitochondrial homeostasis required for Treg maintenance, and is induced in liver by IL-6 to drive FGF23 production in AKI, establishing two distinct in vivo physiological axes.","evidence":"Conditional knockout with metabolic readouts in Tregs; liver-specific depletion, overexpression, inverse agonist, and IL-6 neutralization in AKI mice","pmids":["34156979","33853949"],"confidence":"High","gaps":["Direct ERRγ target genes mediating Treg mitochondrial program not enumerated","Direct binding to the FGF23 promoter not shown"]},{"year":2022,"claim":"Identified RB1 as a direct negative regulator of ESRRG and showed ESRRG drives hypoxic retinoblastoma cell survival, framing it as an actionable dependency when RB1 is lost.","evidence":"Protein interaction assay, genomic/single-cell transcriptomics, and ESRRG depletion/inhibition with cell-death readout in retinoblastoma","pmids":["35984874"],"confidence":"Medium","gaps":["Interaction interface and stoichiometry not detailed","Direct ERRγ targets in retinogenesis/oxygen metabolism not mapped"]},{"year":2023,"claim":"Showed ERRγ directly represses PKM2 to suppress glycolysis in esophageal carcinoma, defining a direct transcriptional mechanism for its tumor-suppressive metabolic effect.","evidence":"Promoter luciferase assay, expression manipulation, and glycolysis metabolic assays with DY131 agonist in ESCC cells","pmids":["37679788"],"confidence":"Medium","gaps":["ChIP-level promoter occupancy not shown","Single lab"]},{"year":2024,"claim":"Established ESRRG as a direct activator of the KCNN1 potassium channel gene in sensory neurons, providing a transcriptional mechanism for nerve-injury nociceptive hypersensitivity.","evidence":"ChIP, siRNA, AAV rescue, electrophysiology, and behavioral pain assays in mouse DRG/nerve-injury models","pmids":["38912580"],"confidence":"High","gaps":["Upstream signals reducing ESRRG after nerve injury not defined","Other DRG targets not surveyed"]},{"year":2025,"claim":"Expanded the direct target repertoire to PDE3B (airway inflammation) and HSD11B2 (neuronal mitochondrial integrity), and implicated de novo ESRRG variants in a human disorder of cell proliferation control.","evidence":"Luciferase/ChIP-PCR and inverse-agonist studies in asthma and AD models; ERRE reporter and proliferation assays of patient variants in ESRRG-KO HEK293T cells","pmids":["40153608","41197937","41265451"],"confidence":"High","gaps":["Genotype-phenotype spectrum of the human disorder not fully characterized","Whether variants act as gain or loss varies by assay readout"]},{"year":2026,"claim":"Identified the TRPS1-ESRRG axis as essential for zygotic genome activation and blastocyst formation, and confirmed ESRRG's role in trophoblast mitochondrial function and placental competence.","evidence":"Embryo knockdown with global transcription and developmental staging plus TRPS1 promoter binding; trophoblast functional and mitochondrial assays with in vivo abortion model","pmids":["42248279","41623023"],"confidence":"Medium","gaps":["Direct ESRRG targets driving ZGA not fully defined","Single-lab abstract-level mechanistic detail"]},{"year":null,"claim":"Whether ERRγ has a true endogenous ligand and how its constitutive activity is dynamically modulated in vivo across these diverse tissues remains unresolved.","evidence":"No timeline study identifies an endogenous activating ligand","pmids":[],"confidence":"Low","gaps":["No endogenous ligand identified","Tissue-specific coregulator complement undefined","Unified model linking metabolic and developmental roles absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,9,11,12,13,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11,12,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,11,12,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,7,9,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,7,17]}],"complexes":[],"partners":["RB1","TRPS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62508","full_name":"Estrogen-related receptor gamma","aliases":["ERR gamma-2","Estrogen receptor-related protein 3","Nuclear receptor subfamily 3 group B member 3"],"length_aa":458,"mass_kda":51.3,"function":"Orphan receptor that acts as a transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P62508/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESRRG","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ESRRG","total_profiled":1310},"omim":[{"mim_id":"615921","title":"PPARGC1- AND ESRR-INDUCED REGULATOR, MUSCLE, 1; PERM1","url":"https://www.omim.org/entry/615921"},{"mim_id":"611882","title":"PROLINE-RICH NUCLEAR RECEPTOR COACTIVATOR 2; PNRC2","url":"https://www.omim.org/entry/611882"},{"mim_id":"608886","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, BETA; PPARGC1B","url":"https://www.omim.org/entry/608886"},{"mim_id":"602969","title":"ESTROGEN-RELATED RECEPTOR, GAMMA; ESRRG","url":"https://www.omim.org/entry/602969"},{"mim_id":"600189","title":"TLE FAMILY MEMBER 1, TRANSCRIPTIONAL COREPRESSOR; TLE1","url":"https://www.omim.org/entry/600189"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":27.1},{"tissue":"parathyroid gland","ntpm":43.5},{"tissue":"retina","ntpm":33.5},{"tissue":"stomach 1","ntpm":33.1}],"url":"https://www.proteinatlas.org/search/ESRRG"},"hgnc":{"alias_symbol":["NR3B3","ERRg","ERR-gamma"],"prev_symbol":[]},"alphafold":{"accession":"P62508","domains":[{"cath_id":"3.30.50.10","chopping":"136-196","consensus_level":"high","plddt":94.6016,"start":136,"end":196},{"cath_id":"1.10.565.10","chopping":"237-455","consensus_level":"high","plddt":95.328,"start":237,"end":455}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62508","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62508-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62508-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESRRG","jax_strain_url":"https://www.jax.org/strain/search?query=ESRRG"},"sequence":{"accession":"P62508","fasta_url":"https://rest.uniprot.org/uniprotkb/P62508.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62508/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62508"}},"corpus_meta":[{"pmid":"17761695","id":"PMC_17761695","title":"Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma.","date":"2007","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17761695","citation_count":189,"is_preprint":false},{"pmid":"19304792","id":"PMC_19304792","title":"Placenta expressing the greatest quantity of bisphenol A receptor ERR{gamma} among the human reproductive tissues: Predominant expression of type-1 ERRgamma isoform.","date":"2009","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19304792","citation_count":71,"is_preprint":false},{"pmid":"23589079","id":"PMC_23589079","title":"miR-205 promotes tumor proliferation and invasion through targeting ESRRG in endometrial carcinoma.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23589079","citation_count":63,"is_preprint":false},{"pmid":"21138943","id":"PMC_21138943","title":"Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21138943","citation_count":29,"is_preprint":false},{"pmid":"33853949","id":"PMC_33853949","title":"Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33853949","citation_count":28,"is_preprint":false},{"pmid":"34156979","id":"PMC_34156979","title":"Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34156979","citation_count":27,"is_preprint":false},{"pmid":"32571331","id":"PMC_32571331","title":"Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32571331","citation_count":24,"is_preprint":false},{"pmid":"31069202","id":"PMC_31069202","title":"Placental ESRRG-CYP19A1 Expressions and Circulating 17-Beta Estradiol in IUGR Pregnancies.","date":"2019","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/31069202","citation_count":20,"is_preprint":false},{"pmid":"35984874","id":"PMC_35984874","title":"RB1 loss triggers dependence on ESRRG in retinoblastoma.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35984874","citation_count":18,"is_preprint":false},{"pmid":"29535761","id":"PMC_29535761","title":"A Genome-Wide Search for Gene-Environment Effects in Isolated Cleft Lip with or without Cleft Palate Triads Points to an Interaction between Maternal Periconceptional Vitamin Use and Variants in ESRRG.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29535761","citation_count":18,"is_preprint":false},{"pmid":"37679788","id":"PMC_37679788","title":"ESRRG-PKM2 axis reprograms metabolism to suppress esophageal squamous carcinoma progression and enhance anti-PD-1 therapy efficacy.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37679788","citation_count":17,"is_preprint":false},{"pmid":"27113491","id":"PMC_27113491","title":"Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits.","date":"2016","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/27113491","citation_count":15,"is_preprint":false},{"pmid":"32595605","id":"PMC_32595605","title":"ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation.","date":"2020","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32595605","citation_count":14,"is_preprint":false},{"pmid":"35220427","id":"PMC_35220427","title":"Sex-specific effects of bisphenol A on the signaling pathway of ESRRG in the human placenta†.","date":"2022","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/35220427","citation_count":14,"is_preprint":false},{"pmid":"19949424","id":"PMC_19949424","title":"Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice.","date":"2009","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/19949424","citation_count":13,"is_preprint":false},{"pmid":"21153485","id":"PMC_21153485","title":"A long AAAG repeat allele in the 5' UTR of the ERR-γ gene is correlated with breast cancer predisposition and drives promoter activity in MCF-7 breast cancer cells.","date":"2010","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/21153485","citation_count":12,"is_preprint":false},{"pmid":"27417234","id":"PMC_27417234","title":"Estrogen-related receptor (ERR) γ protects against puromycin aminonucleoside-induced podocyte apoptosis by targeting PI3K/Akt signaling.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27417234","citation_count":10,"is_preprint":false},{"pmid":"39235305","id":"PMC_39235305","title":"Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma Beyond Fusions Between MYB/MYBL1 and NFIB Genes.","date":"2024","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39235305","citation_count":6,"is_preprint":false},{"pmid":"28852080","id":"PMC_28852080","title":"Influence of estrogen-related receptor γ (ESRRG) rs1890552 A > G polymorphism on changes in fasting glucose and arterial stiffness.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28852080","citation_count":5,"is_preprint":false},{"pmid":"38912580","id":"PMC_38912580","title":"ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38912580","citation_count":3,"is_preprint":false},{"pmid":"40153608","id":"PMC_40153608","title":"Esrrg Inhibition Protects against Fine Particulate Matter-induced Asthma Aggravation by Reducing Pde3b.","date":"2025","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40153608","citation_count":2,"is_preprint":false},{"pmid":"35623593","id":"PMC_35623593","title":"Molecular mechanism of the ESRRG-PERM1-CKMT2 signal axis in ovariectomized female rats with OSAHS.","date":"2022","source":"Transplant 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{\n      \"year\": 2007,\n      \"finding\": \"BPA binds to the ERRγ ligand-binding domain (LBD) with high affinity (KD = 5.5 nM). Crystal structure of the ERRγ-LBD/BPA complex revealed that BPA is anchored by hydrogen bonds between its two phenol-hydroxyl groups and residues Glu275, Arg316, and Asn346, with additional hydrophobic contacts especially with Tyr326. BPA binding preserves the active conformation of helix 12, thereby maintaining ERRγ constitutive transcriptional activity. ERRγ behaves as a constitutive activator of transcription in the absence of a known endogenous ligand.\",\n      \"method\": \"X-ray crystallography of ERRγ-LBD/BPA complex; prior biochemical binding assay (KD determination)\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with atomic resolution of ligand-receptor interaction, combined with prior biochemical binding assay; mechanistically rigorous single study\",\n      \"pmids\": [\"17761695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An ERRγ isoform (type-1) bearing an additional 23-mer amino-acid sequence at the N-terminus elevates ERRγ basal constitutive transcriptional activity by approximately 50%, as demonstrated by luciferase reporter gene assay. Placenta exclusively expresses this type-1 isoform among ERRγ protein isoforms.\",\n      \"method\": \"Luciferase reporter gene assay; real-time PCR; identification of ERRγ mRNA variants and protein isoforms in human reproductive tissues\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay demonstrating isoform-specific activity difference; single lab, single study\",\n      \"pmids\": [\"19304792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Esrrg protein is detected in early ureteric ducts (cytoplasmic/sub-membranous) and in developing nephrons (nuclear localization). siRNA-mediated knockdown and small-molecule agonist-induced aberrant activation of Esrrg in embryonic mouse kidney cultures both caused severe abnormality of early branching events of the ureteric duct. Esrrg homozygous knockout mice (Esrrg−/−) displayed agenesis of the renal papilla with otherwise normal cortex and medulla development, establishing Esrrg as required for ureteric bud branching prior to nephrogenesis onset.\",\n      \"method\": \"Immunostaining for subcellular localization; siRNA knockdown in embryonic kidney explant culture; small-molecule agonist treatment; targeted gene knockout mouse model (Esrrg−/−)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (siRNA, pharmacological, genetic KO) with defined morphological phenotype; in vivo validation\",\n      \"pmids\": [\"21138943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERRγ expression is induced in the liver during acute kidney injury (AKI) by upstream IL-6 signaling. Hepatic ERRγ overexpression is sufficient to induce hepatic FGF23 production. Liver-specific depletion of ERRγ or treatment with an inverse ERRγ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in folic acid-induced AKI mice. IL-6 neutralizing antibody reduced ERRγ-mediated FGF23 production, confirming the IL-6 → ERRγ → FGF23 axis.\",\n      \"method\": \"Ectopic overexpression; liver-specific genetic depletion; inverse agonist pharmacological inhibition; IL-6 neutralizing antibody; folic acid-induced AKI mouse model; plasma FGF23 measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic overexpression, liver-specific KO, pharmacological inhibitor, antibody neutralization) in vivo, with defined molecular pathway placement\",\n      \"pmids\": [\"33853949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Esrrg controls regulatory T cell (Treg) maintenance and function through mitochondrial homeostasis. Esrrg-deficient Tregs exhibit dysregulated mitochondria with decreased oxygen consumption, ATP production, and NAD+ levels. Esrrg deficiency also leads to decreased phosphatidylinositol and TGF-β signaling and increased mTOR complex 1 activation in Tregs, impaired differentiation into follicular Tregs, and enhanced follicular helper T cell responses, resulting in global T cell activation and autoimmunity in aged mice.\",\n      \"method\": \"Conditional knockout mouse model; mitochondrial oxygen consumption assay; ATP and NAD+ quantification; phospho-signaling pathway analysis; T cell subset phenotyping; ESRRG knockdown in Jurkat cells with metabolic readout\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal metabolic and immunological readouts; in vivo autoimmunity phenotype and in vitro metabolic validation\",\n      \"pmids\": [\"34156979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation in retinoblastoma cells. ESRRG regulates genes involved in retinogenesis and oxygen metabolism and is preferentially expressed in hypoxic retinoblastoma cells in vivo. Depletion or inhibition of ESRRG causes marked retinoblastoma cell death, which is exacerbated under hypoxia.\",\n      \"method\": \"Protein interaction assay (RB1-ESRRG direct interaction); whole exome/transcriptome/single-cell transcriptome genomic analyses; ESRRG depletion/inhibition with cell death readout; in vivo tumor hypoxia expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction and functional depletion with defined phenotype; single lab study, abstract does not fully detail interaction method rigor\",\n      \"pmids\": [\"35984874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sophoridine promotes β-catenin degradation by enhancing ESRRG expression in gastric cancer cells, independently of ubiquitination-proteasome pathway, TRIM33-mediated GSK3β-independent pathway, or altered GSK3β activity. ESRRG-mediated β-catenin degradation underlies the tumor-suppressive effects of sophoridine.\",\n      \"method\": \"siRNA transfection; nuclear/cytoplasmic fractionation; western blot; CCK-8, EDU, colony forming, transwell, and flow cytometry assays in AGS and SGC7901 cells\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with siRNA and fractionation, multiple cell-based functional assays; single lab\",\n      \"pmids\": [\"32571331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ESRRG and PERM1 are involved in the PGC1α transcriptional network to positively regulate mitochondrial capacity in adipocytes. Increased expression of ESRRG supports the formation of brown or brite/beige adipocytes both in vitro and in vivo, indicating ESRRG is an early inducer and important regulator of brite/beige adipocyte formation and mitochondrial conversion.\",\n      \"method\": \"Transcriptome profiling of inguinal adipocytes during cold exposure; in vitro and in vivo overexpression experiments; functional measurement of mitochondrial uncoupled respiration\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro overexpression with functional mitochondrial readout; transcriptome supporting data; single lab\",\n      \"pmids\": [\"32595605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERRγ overexpression attenuates puromycin aminonucleoside (PAN)-induced podocyte apoptosis and stimulates PI3K/Akt signaling (increased expression of PI3K subunits p85α and p110α and phosphorylated Akt). Conversely, ERRγ siRNA silencing causes podocyte apoptosis with increased injury markers (B7-1, cathepsin L) and decreased nephrin. A specific PI3K inhibitor (LY294002) entirely reversed the anti-apoptotic effect of ERRγ, establishing PI3K/Akt as the downstream effector pathway.\",\n      \"method\": \"siRNA knockdown; overexpression; PI3K inhibitor rescue experiment; western blot for signaling pathway components; apoptosis assay; in vivo PAN-treated rat kidney model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue to establish pathway; single lab\",\n      \"pmids\": [\"27417234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ESRRG directly interacts with the PKM2 promoter to inhibit its transcriptional activity in esophageal squamous cell carcinoma (ESCC) cells, thereby suppressing glycolysis (Warburg effect). The ESRRG-specific agonist DY131 inhibits ESCC cell proliferation and glycolysis by modulating glycolysis pathway genes, and also modulates lactate regulation relevant to immune checkpoint activity.\",\n      \"method\": \"Promoter luciferase assay; altered ESRRG expression in ESCC cell lines; metabolic assays for glycolysis; DY131 agonist treatment; bioinformatics analysis\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and functional metabolic readout; single lab, abstract-level detail on methods\",\n      \"pmids\": [\"37679788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BPA affects the ESRRG signaling pathway in a sex-specific manner in human placentas: BPA (1 µM, 24 h) increased ESRRG mRNA and protein in female placentas but decreased them in male placentas (at 1 nM or 1 µM, 48 h). Downstream ESRRG targets HSD17B1 and PLAC1 were correspondingly altered in a sex-specific pattern. BPA treatment did not affect proliferation, apoptosis, or syncytiotrophoblast differentiation.\",\n      \"method\": \"Placental villous explant culture with BPA; mRNA and protein quantification; sex-stratified analysis of ESRRG pathway constituents\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo human tissue explant with mRNA and protein quantification at multiple doses and timepoints; single lab, sex-stratified analysis\",\n      \"pmids\": [\"35220427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESRRG functions as a transcription factor that directly binds the Kcnn1 (KCNN1) gene promoter in dorsal root ganglion (DRG) neurons. Peripheral nerve injury reduces DRG ESRRG expression, leading to reduced KCNN1 transcription. This downregulation decreases total potassium voltage currents and afterhyperpolarization currents, increasing neuronal excitability and nociceptive hypersensitivity. Rescuing KCNN1 expression prevented CCI-induced pain behaviors without affecting locomotion or acute pain.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay demonstrating ESRRG binding to Kcnn1 promoter; siRNA-mediated knockdown; AAV-mediated rescue; electrophysiology (potassium current and AHP measurement); behavioral pain assays in CCI and L4 ligation mouse models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding by ChIP, electrophysiological validation, in vivo genetic rescue with defined molecular and behavioral phenotype; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38912580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESRRG binds to the Pde3b (phosphodiesterase 3B) promoter, as demonstrated by dual luciferase reporter assay and chromatin immunoprecipitation PCR. Esrrg inhibition (by AAV-shEsrrg or inverse agonist GSK5182) reduces Pde3b expression and alleviates airway inflammation in PM2.5-aggravated asthmatic mice and in isolated mouse tracheobronchial epithelial cells.\",\n      \"method\": \"Dual luciferase reporter assay; chromatin immunoprecipitation PCR; AAV-mediated shRNA knockdown; pharmacological inverse agonist (GSK5182); in vivo asthma-PM2.5 mouse model; in vitro tracheobronchial epithelial cell model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct promoter binding confirmed by ChIP and reporter assay, in vivo and in vitro functional validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40153608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo heterozygous variants in ESRRG (located in DNA-binding and ligand-binding domains) reduce transcriptional activity at ERR response elements (ERRE) as assessed by reporter gene assay in ESRRG-knockout HEK293T cells. ESRRG knockout increases cell proliferation, and wild-type ESRRG overexpression restores normal proliferation, while the identified disease variants do not. All identified variants retain correct nuclear localization. These findings implicate ESRRG gain-of-function transcriptional activity in cell proliferation control.\",\n      \"method\": \"ERRE luciferase reporter gene assay in ESRRG-KO HEK293T cells (transient transfection of each variant vs. wild-type); cell proliferation assay; immunofluorescence for subcellular localization; molecular modeling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and proliferation assay with multiple patient-derived variants in defined KO background; single lab, abstract-level method description\",\n      \"pmids\": [\"41265451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESRRG mediates HSD11B2 transcription; propofol suppresses ESRRG expression in hippocampal neurons of 3xTg-AD mice, thereby reducing HSD11B2 and causing mitochondrial dysfunction (decreased membrane potential, increased cytochrome C release, increased p-DRP1). ESRRG overexpression (AAV-mediated) mitigated propofol-induced mitochondrial dysfunction and postoperative cognitive dysfunction, but these effects were reversed by HSD11B2 knockdown, establishing ESRRG → HSD11B2 as a functional transcriptional axis.\",\n      \"method\": \"AAV-mediated ESRRG overexpression; HSD11B2 knockdown; in vivo behavioral testing (Morris water maze); mitochondrial function assays (MMP, ROS, cytochrome C, p-DRP1); in vitro HT22 neuronal cell experiments\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro genetic manipulation with mechanistic rescue experiment establishing transcriptional axis; single lab\",\n      \"pmids\": [\"41197937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ESRRG is uniquely and highly expressed at the 2-cell embryo stage in mice and is essential for blastocyst formation. ESRRG knockdown reduces global transcriptional activity in 2-cell embryos, impairing zygotic genome activation (ZGA) and the 2-cell to 4-cell transition. The transcription factor TRPS1 directly binds to the Esrrg promoter to regulate its expression. The TRPS1-ESRRG axis controls ZGA factors including Sp1 and tankyrase 2.\",\n      \"method\": \"siRNA/morpholino knockdown of Esrrg in mouse preimplantation embryos; global transcriptional activity assay; ChIP or equivalent assay showing TRPS1 binding to Esrrg promoter; embryo developmental staging\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo embryo knockdown with transcriptional and developmental phenotype, upstream regulator identified; single lab, abstract-level method detail\",\n      \"pmids\": [\"42248279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Esrrg expression is significantly upregulated (2.36-fold) by fenofibrate treatment in ApoA-I transgenic mice and shows significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating a role for ERRγ in mediating fenofibrate-induced activation of specific lipid metabolism target genes.\",\n      \"method\": \"Global gene expression profiling (microarray) in ApoA-I transgenic mice treated with fenofibrate; bioinformatics correlation analysis\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — correlational expression profiling only; no direct functional manipulation of ESRRG; single study\",\n      \"pmids\": [\"19949424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ESRRG downregulation in trophoblasts impairs mitochondrial function (decreased ATP, abnormal mitochondrial morphology) and reduces proliferation, invasion, migration, and tube formation in HTR-8/SVneo cells. ESRRG overexpression in a lipopolysaccharide-induced abortion mouse model improved trophoblast functionality and increased the number of retained embryos in the uterus.\",\n      \"method\": \"CCK8 and Transwell assays; MitoSOX staining; JC-1 mitochondrial membrane potential assay; ATP quantification; transmission electron microscopy; in vivo mouse overexpression model\",\n      \"journal\": \"Annals of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mitochondrial and functional assays with in vivo validation; single lab\",\n      \"pmids\": [\"41623023\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESRRG (ERRγ) is an orphan nuclear receptor that functions as a constitutive transcriptional activator, binding to ERR response elements (ERREs) to regulate genes involved in mitochondrial metabolism, lipid homeostasis, steroidogenesis, and developmental programs; its LBD adopts an active conformation without a known endogenous ligand and is a high-affinity receptor for the endocrine disruptor BPA; it directly controls target gene transcription by binding promoters of KCNN1, PKM2, PDE3B, and HSD11B2, and is negatively regulated by direct interaction with RB1; it is required for ureteric bud branching morphogenesis, renal papilla formation, Treg mitochondrial homeostasis, zygotic genome activation, podocyte survival via PI3K/Akt signaling, and hepatic FGF23 production downstream of IL-6 in acute kidney injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESRRG (ERRγ) is an orphan nuclear receptor that acts as a constitutive transcriptional activator at ERR response elements, coordinating mitochondrial metabolic programs, developmental transitions, and tissue-specific gene expression across multiple organ systems [#0, #13]. Its ligand-binding domain adopts an active conformation in the absence of a known endogenous ligand, and it serves as a high-affinity receptor for the endocrine disruptor bisphenol A (KD = 5.5 nM), which is anchored within the LBD by hydrogen bonds to Glu275, Arg316, and Asn346 and stabilizes the active helix-12 conformation [#0]. ERRγ exerts its effects largely by directly binding target gene promoters: it represses the glycolytic gene PKM2 to suppress the Warburg effect in carcinoma cells [#9], represses PDE3B in airway epithelium [#12], and activates KCNN1 in sensory neurons to control potassium currents and nociceptive excitability [#11] and HSD11B2 in hippocampal neurons to maintain mitochondrial integrity [#14]. A recurrent theme across tissues is its control of mitochondrial homeostasis and oxidative capacity — in regulatory T cells, where loss disrupts respiration and ATP/NAD+ levels and provokes autoimmunity [#4], in beige/brown adipocytes through the PGC1α network [#7], and in trophoblasts [#17]. ERRγ is required for ureteric bud branching and renal papilla formation [#2], for zygotic genome activation in 2-cell embryos downstream of TRPS1 [#15], and is induced in the liver by IL-6 to drive FGF23 production during acute kidney injury [#3]. Its transcriptional activity is held in check by direct interaction with RB1 [#5]. De novo heterozygous ESRRG variants in the DNA- and ligand-binding domains alter transcriptional activity and dysregulate cell proliferation, implicating the receptor in a human developmental disorder [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the structural basis for ERRγ's constitutive activity and its capture by an environmental xenoestrogen, answering how a receptor without an endogenous ligand stays active and how BPA hijacks it.\",\n      \"evidence\": \"X-ray crystallography of the ERRγ-LBD/BPA complex plus biochemical binding (KD determination)\",\n      \"pmids\": [\"17761695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous ligand identified\", \"Does not address physiological consequences of BPA binding in tissues\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that N-terminal isoform variation tunes ERRγ's basal transcriptional output and that the placenta selectively expresses a higher-activity isoform, linking isoform choice to tissue-specific activity.\",\n      \"evidence\": \"Luciferase reporter assay and RT-PCR isoform mapping in human reproductive tissues\",\n      \"pmids\": [\"19304792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes affected by the activity difference not defined\", \"Single-study reporter quantification\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined ERRγ as an in vivo developmental regulator, demonstrating it is required for ureteric bud branching and renal papilla formation.\",\n      \"evidence\": \"siRNA, pharmacological agonist, and germline knockout in embryonic mouse kidney\",\n      \"pmids\": [\"21138943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in branching morphogenesis not identified\", \"Mechanism linking activity to branching unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ERRγ to podocyte survival, establishing PI3K/Akt as the effector pathway through which it protects against injury-induced apoptosis.\",\n      \"evidence\": \"Gain/loss-of-function with PI3K inhibitor rescue in podocytes and PAN rat model\",\n      \"pmids\": [\"27417234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets upstream of PI3K not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed ERRγ within the PGC1α mitochondrial network as an early inducer of brite/beige adipocyte formation, and separately as a mediator of β-catenin degradation in gastric cancer.\",\n      \"evidence\": \"Adipocyte transcriptome profiling with in vitro/in vivo overexpression and mitochondrial respiration; siRNA and fractionation in gastric cancer cells\",\n      \"pmids\": [\"32595605\", \"32571331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter targets in adipocytes not defined\", \"Mechanism of ESRRG-driven β-catenin degradation not molecularly resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that ERRγ governs mitochondrial homeostasis required for Treg maintenance, and is induced in liver by IL-6 to drive FGF23 production in AKI, establishing two distinct in vivo physiological axes.\",\n      \"evidence\": \"Conditional knockout with metabolic readouts in Tregs; liver-specific depletion, overexpression, inverse agonist, and IL-6 neutralization in AKI mice\",\n      \"pmids\": [\"34156979\", \"33853949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERRγ target genes mediating Treg mitochondrial program not enumerated\", \"Direct binding to the FGF23 promoter not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified RB1 as a direct negative regulator of ESRRG and showed ESRRG drives hypoxic retinoblastoma cell survival, framing it as an actionable dependency when RB1 is lost.\",\n      \"evidence\": \"Protein interaction assay, genomic/single-cell transcriptomics, and ESRRG depletion/inhibition with cell-death readout in retinoblastoma\",\n      \"pmids\": [\"35984874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interface and stoichiometry not detailed\", \"Direct ERRγ targets in retinogenesis/oxygen metabolism not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ERRγ directly represses PKM2 to suppress glycolysis in esophageal carcinoma, defining a direct transcriptional mechanism for its tumor-suppressive metabolic effect.\",\n      \"evidence\": \"Promoter luciferase assay, expression manipulation, and glycolysis metabolic assays with DY131 agonist in ESCC cells\",\n      \"pmids\": [\"37679788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ChIP-level promoter occupancy not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ESRRG as a direct activator of the KCNN1 potassium channel gene in sensory neurons, providing a transcriptional mechanism for nerve-injury nociceptive hypersensitivity.\",\n      \"evidence\": \"ChIP, siRNA, AAV rescue, electrophysiology, and behavioral pain assays in mouse DRG/nerve-injury models\",\n      \"pmids\": [\"38912580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals reducing ESRRG after nerve injury not defined\", \"Other DRG targets not surveyed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the direct target repertoire to PDE3B (airway inflammation) and HSD11B2 (neuronal mitochondrial integrity), and implicated de novo ESRRG variants in a human disorder of cell proliferation control.\",\n      \"evidence\": \"Luciferase/ChIP-PCR and inverse-agonist studies in asthma and AD models; ERRE reporter and proliferation assays of patient variants in ESRRG-KO HEK293T cells\",\n      \"pmids\": [\"40153608\", \"41197937\", \"41265451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype spectrum of the human disorder not fully characterized\", \"Whether variants act as gain or loss varies by assay readout\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the TRPS1-ESRRG axis as essential for zygotic genome activation and blastocyst formation, and confirmed ESRRG's role in trophoblast mitochondrial function and placental competence.\",\n      \"evidence\": \"Embryo knockdown with global transcription and developmental staging plus TRPS1 promoter binding; trophoblast functional and mitochondrial assays with in vivo abortion model\",\n      \"pmids\": [\"42248279\", \"41623023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ESRRG targets driving ZGA not fully defined\", \"Single-lab abstract-level mechanistic detail\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ERRγ has a true endogenous ligand and how its constitutive activity is dynamically modulated in vivo across these diverse tissues remains unresolved.\",\n      \"evidence\": \"No timeline study identifies an endogenous activating ligand\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous ligand identified\", \"Tissue-specific coregulator complement undefined\", \"Unified model linking metabolic and developmental roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 9, 11, 12, 13, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 7, 9, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 7, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RB1\", \"TRPS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}