{"gene":"PPARGC1B","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"PPARGC1B (PERC) selectively coactivates estrogen receptor alpha (ERα) but not ERβ, through a bipartite transcriptional activation domain and two LXXLL motifs that interact with the AF2 domain of ERα in an estrogen-dependent manner.","method":"Transfection-based coactivation assays, LXXLL motif mutagenesis, interaction assays with AF2 domain of ERα","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct interaction mapped via mutagenesis of LXXLL motifs and AF2 domain, multiple orthogonal functional assays in a single focused study","pmids":["11854298"],"is_preprint":false},{"year":2002,"finding":"PPARGC1B (PERC/PGC-1beta) enhances the activity of ERRγ via its constitutive AF-2 domain, with direct protein–protein interaction demonstrated in vitro.","method":"Cell-based transcriptional activation assays, receptor truncation analysis, in vitro interaction assays (direct binding demonstrated)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus cell-based functional assays in single study, multiple orthogonal methods","pmids":["12470660"],"is_preprint":false},{"year":2016,"finding":"PPARGC1B mediates the stimulatory effect of 17β-estradiol on hepatic mitochondrial biogenesis and function; siRNA knockdown of PPARGC1B (but not PGC1A) abolished E2-induced improvements in mitochondrial content and oxidative capacity in HepG2 hepatocytes.","method":"siRNA knockdown in HepG2 cells combined with mitochondrial biogenesis and function assays; ovariectomized rat model with E2 treatment","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-specific knockdown with defined cellular phenotype, supported by in vivo model, single lab","pmids":["27885055"],"is_preprint":false},{"year":2016,"finding":"The PPARGC1B exonic variant +102525A (R265Q) enhances ERα transcriptional coactivation to a greater degree than the +102525G allele, and the +102525A protein coprecipitates more intensely with ERα after 17β-estradiol treatment.","method":"Luciferase reporter assay in 293T cells co-transfected with PPARGC1B variant constructs + ERα + ERE-luciferase; co-precipitation assay with HA-tagged PPARGC1B constructs","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal methods (reporter assay and co-precipitation) in a single study, single lab","pmids":["27027322"],"is_preprint":false},{"year":2018,"finding":"ZFP36L1 post-transcriptionally represses PPARGC1B expression by binding AU-rich elements in PPARGC1B 3'-UTR, and knockdown of PPARGC1B impairs adipogenic differentiation of bone marrow mesenchymal stem cells.","method":"Lentivirus-mediated ZFP36L1 knockdown and overexpression; PPARGC1B knockdown in adipogenesis assays; 3'-UTR AU-rich element analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype, 3'-UTR mechanism established, multiple orthogonal approaches, single lab","pmids":["29993187"],"is_preprint":false},{"year":2024,"finding":"The rs10071329 G/G genotype at the PPARGC1B locus (introduced by CRISPR/Cas9 scarless editing) increases PPARGC1B expression throughout brown adipocyte differentiation (cis-eQTL), leading to greater triglyceride accumulation, higher mitochondria-encoded gene expression, improved basal and norepinephrine-stimulated mitochondrial respiration, and increased norepinephrine-stimulated lipolysis.","method":"CRISPR/Cas9 allelic editing in human brown adipocyte cell line; gene expression analysis; mitochondrial respiration assays; lipolysis assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — scarless CRISPR allelic editing with multiple orthogonal functional readouts (expression, respiration, lipolysis) in a single rigorous study","pmids":["38190589"],"is_preprint":false}],"current_model":"PPARGC1B (PGC-1β/PERC) is a transcriptional coactivator that selectively activates ERα (and ERRγ) through LXXLL motif–AF2 interactions, mediates estrogen-induced mitochondrial biogenesis and function in hepatocytes, promotes adipogenesis in mesenchymal stem cells (regulated post-transcriptionally by ZFP36L1 via its 3'-UTR), and in brown adipocytes drives mitochondrial respiration and norepinephrine-stimulated lipolysis as determined by CRISPR allelic editing of a cis-eQTL variant."},"narrative":{"mechanistic_narrative":"PPARGC1B (PGC-1β/PERC) is a transcriptional coactivator that drives mitochondrial biogenesis and energy-metabolic programs in hepatocytes and adipocytes [PMID:27885055, PMID:38190589]. It selectively coactivates estrogen receptor alpha (ERα), but not ERβ, through two LXXLL motifs that engage the ERα AF2 domain in an estrogen-dependent manner, and it likewise enhances ERRγ activity via the receptor's constitutive AF-2 domain [PMID:11854298, PMID:12470660]. Through this ERα-coactivating function, PPARGC1B mediates the stimulatory effect of 17β-estradiol on hepatic mitochondrial content and oxidative capacity, an effect specific to PPARGC1B rather than PGC1A [PMID:27885055]. A coding variant (R265Q) increases ERα coactivation and estradiol-dependent association with ERα, linking sequence variation to coactivator output [PMID:27027322]. In adipogenic and brown-adipocyte contexts, PPARGC1B is required for differentiation and is post-transcriptionally repressed by ZFP36L1 binding to AU-rich elements in its 3'-UTR [PMID:29993187]; CRISPR allelic editing of a cis-eQTL variant (rs10071329 G/G) that raises PPARGC1B expression increases triglyceride accumulation, mitochondria-encoded gene expression, basal and norepinephrine-stimulated respiration, and norepinephrine-stimulated lipolysis, establishing a dose-dependent role in brown adipocyte mitochondrial function and lipolysis [PMID:38190589].","teleology":[{"year":2002,"claim":"Established that PPARGC1B is a nuclear-receptor coactivator with selectivity, answering which receptors it engages and through what interface.","evidence":"Transfection coactivation assays with LXXLL motif and ERα AF2 domain mutagenesis; receptor truncation and in vitro binding for ERRγ","pmids":["11854298","12470660"],"confidence":"High","gaps":["Endogenous target genes of ERα/ERRγ coactivation not defined","Selectivity for ERα over ERβ mechanistically explained only at the LXXLL/AF2 level"]},{"year":2016,"claim":"Connected PPARGC1B coactivator activity to a physiological output by showing it is specifically required for estrogen-induced hepatic mitochondrial biogenesis.","evidence":"siRNA knockdown of PPARGC1B versus PGC1A in HepG2 cells with mitochondrial assays, plus ovariectomized rat E2 model","pmids":["27885055"],"confidence":"Medium","gaps":["Direct target genes downstream of E2/PPARGC1B not mapped","Single-lab evidence"]},{"year":2016,"claim":"Demonstrated that a coding variant modulates coactivator strength, linking PPARGC1B sequence variation to ERα interaction and transcriptional output.","evidence":"Luciferase ERE-reporter assays in 293T and co-precipitation with HA-tagged variant constructs","pmids":["27027322"],"confidence":"Medium","gaps":["Physiological/in vivo consequence of R265Q not established","Mechanism by which R265Q enhances ERα binding unresolved"]},{"year":2018,"claim":"Identified post-transcriptional control of PPARGC1B and a requirement for it in adipogenesis, defining an upstream regulatory layer.","evidence":"ZFP36L1 knockdown/overexpression, 3'-UTR AU-rich element analysis, and PPARGC1B knockdown in MSC adipogenesis assays","pmids":["29993187"],"confidence":"Medium","gaps":["Direct ZFP36L1–3'UTR binding shown indirectly","Coactivation targets driving adipogenesis not specified"]},{"year":2024,"claim":"Established a causal, dose-dependent role for PPARGC1B in brown adipocyte mitochondrial function and lipolysis using allelic editing of a cis-regulatory variant.","evidence":"Scarless CRISPR/Cas9 editing of rs10071329 in a human brown adipocyte line with expression, respiration, and lipolysis readouts","pmids":["38190589"],"confidence":"High","gaps":["Transcription factor mediating the cis-eQTL effect not identified","In vivo metabolic consequence in humans not tested"]},{"year":null,"claim":"The genome-wide direct target genes of PPARGC1B coactivation and how its activity is integrated across hepatic versus adipose tissues remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No ChIP/genomic target map in the corpus","Tissue-specific receptor partners beyond ERα/ERRγ uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5]}],"complexes":[],"partners":["ESR1","ESRRG","ZFP36L1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86YN6","full_name":"Peroxisome proliferator-activated receptor gamma coactivator 1-beta","aliases":["PGC-1-related estrogen receptor alpha coactivator"],"length_aa":1023,"mass_kda":113.2,"function":"Plays a role of stimulator of transcription factors and nuclear receptors activities. Activates transcriptional activity of estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and glucocorticoid receptor in the presence of glucocorticoids. May play a role in constitutive non-adrenergic-mediated mitochondrial biogenesis as suggested by increased basal oxygen consumption and mitochondrial number when overexpressed. May be involved in fat oxidation and non-oxidative glucose metabolism and in the regulation of energy expenditure. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86YN6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPARGC1B","classification":"Not Classified","n_dependent_lines":497,"n_total_lines":1208,"dependency_fraction":0.41142384105960267},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPARGC1B","total_profiled":1310},"omim":[{"mim_id":"619511","title":"ZINC FINGER PROTEIN 354C; ZNF354C","url":"https://www.omim.org/entry/619511"},{"mim_id":"615921","title":"PPARGC1- AND ESRR-INDUCED REGULATOR, MUSCLE, 1; PERM1","url":"https://www.omim.org/entry/615921"},{"mim_id":"609059","title":"PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 2; PNPLA2","url":"https://www.omim.org/entry/609059"},{"mim_id":"608886","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, BETA; PPARGC1B","url":"https://www.omim.org/entry/608886"},{"mim_id":"604517","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, ALPHA; PPARGC1A","url":"https://www.omim.org/entry/604517"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":11.2}],"url":"https://www.proteinatlas.org/search/PPARGC1B"},"hgnc":{"alias_symbol":["PERC","PGC1B","PPARAGCIβ"],"prev_symbol":[]},"alphafold":{"accession":"Q86YN6","domains":[{"cath_id":"3.30.70.330","chopping":"892-981","consensus_level":"medium","plddt":86.4559,"start":892,"end":981}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YN6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YN6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YN6-F1-predicted_aligned_error_v6.png","plddt_mean":50.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPARGC1B","jax_strain_url":"https://www.jax.org/strain/search?query=PPARGC1B"},"sequence":{"accession":"Q86YN6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YN6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YN6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YN6"}},"corpus_meta":[{"pmid":"11854298","id":"PMC_11854298","title":"The 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siRNA knockdown of PPARGC1B (but not PGC1A) abolished E2-induced improvements in mitochondrial content and oxidative capacity in HepG2 hepatocytes.\",\n      \"method\": \"siRNA knockdown in HepG2 cells combined with mitochondrial biogenesis and function assays; ovariectomized rat model with E2 treatment\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-specific knockdown with defined cellular phenotype, supported by in vivo model, single lab\",\n      \"pmids\": [\"27885055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PPARGC1B exonic variant +102525A (R265Q) enhances ERα transcriptional coactivation to a greater degree than the +102525G allele, and the +102525A protein coprecipitates more intensely with ERα after 17β-estradiol treatment.\",\n      \"method\": \"Luciferase reporter assay in 293T cells co-transfected with PPARGC1B variant constructs + ERα + ERE-luciferase; co-precipitation assay with HA-tagged PPARGC1B constructs\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal methods (reporter assay and co-precipitation) in a single study, single lab\",\n      \"pmids\": [\"27027322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFP36L1 post-transcriptionally represses PPARGC1B expression by binding AU-rich elements in PPARGC1B 3'-UTR, and knockdown of PPARGC1B impairs adipogenic differentiation of bone marrow mesenchymal stem cells.\",\n      \"method\": \"Lentivirus-mediated ZFP36L1 knockdown and overexpression; PPARGC1B knockdown in adipogenesis assays; 3'-UTR AU-rich element analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype, 3'-UTR mechanism established, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"29993187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The rs10071329 G/G genotype at the PPARGC1B locus (introduced by CRISPR/Cas9 scarless editing) increases PPARGC1B expression throughout brown adipocyte differentiation (cis-eQTL), leading to greater triglyceride accumulation, higher mitochondria-encoded gene expression, improved basal and norepinephrine-stimulated mitochondrial respiration, and increased norepinephrine-stimulated lipolysis.\",\n      \"method\": \"CRISPR/Cas9 allelic editing in human brown adipocyte cell line; gene expression analysis; mitochondrial respiration assays; lipolysis assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — scarless CRISPR allelic editing with multiple orthogonal functional readouts (expression, respiration, lipolysis) in a single rigorous study\",\n      \"pmids\": [\"38190589\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPARGC1B (PGC-1β/PERC) is a transcriptional coactivator that selectively activates ERα (and ERRγ) through LXXLL motif–AF2 interactions, mediates estrogen-induced mitochondrial biogenesis and function in hepatocytes, promotes adipogenesis in mesenchymal stem cells (regulated post-transcriptionally by ZFP36L1 via its 3'-UTR), and in brown adipocytes drives mitochondrial respiration and norepinephrine-stimulated lipolysis as determined by CRISPR allelic editing of a cis-eQTL variant.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPARGC1B (PGC-1β/PERC) is a transcriptional coactivator that drives mitochondrial biogenesis and energy-metabolic programs in hepatocytes and adipocytes [#2, #5]. It selectively coactivates estrogen receptor alpha (ERα), but not ERβ, through two LXXLL motifs that engage the ERα AF2 domain in an estrogen-dependent manner, and it likewise enhances ERRγ activity via the receptor's constitutive AF-2 domain [#0, #1]. Through this ERα-coactivating function, PPARGC1B mediates the stimulatory effect of 17β-estradiol on hepatic mitochondrial content and oxidative capacity, an effect specific to PPARGC1B rather than PGC1A [#2]. A coding variant (R265Q) increases ERα coactivation and estradiol-dependent association with ERα, linking sequence variation to coactivator output [#3]. In adipogenic and brown-adipocyte contexts, PPARGC1B is required for differentiation and is post-transcriptionally repressed by ZFP36L1 binding to AU-rich elements in its 3'-UTR [#4]; CRISPR allelic editing of a cis-eQTL variant (rs10071329 G/G) that raises PPARGC1B expression increases triglyceride accumulation, mitochondria-encoded gene expression, basal and norepinephrine-stimulated respiration, and norepinephrine-stimulated lipolysis, establishing a dose-dependent role in brown adipocyte mitochondrial function and lipolysis [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that PPARGC1B is a nuclear-receptor coactivator with selectivity, answering which receptors it engages and through what interface.\",\n      \"evidence\": \"Transfection coactivation assays with LXXLL motif and ERα AF2 domain mutagenesis; receptor truncation and in vitro binding for ERRγ\",\n      \"pmids\": [\"11854298\", \"12470660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes of ERα/ERRγ coactivation not defined\", \"Selectivity for ERα over ERβ mechanistically explained only at the LXXLL/AF2 level\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PPARGC1B coactivator activity to a physiological output by showing it is specifically required for estrogen-induced hepatic mitochondrial biogenesis.\",\n      \"evidence\": \"siRNA knockdown of PPARGC1B versus PGC1A in HepG2 cells with mitochondrial assays, plus ovariectomized rat E2 model\",\n      \"pmids\": [\"27885055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target genes downstream of E2/PPARGC1B not mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that a coding variant modulates coactivator strength, linking PPARGC1B sequence variation to ERα interaction and transcriptional output.\",\n      \"evidence\": \"Luciferase ERE-reporter assays in 293T and co-precipitation with HA-tagged variant constructs\",\n      \"pmids\": [\"27027322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological/in vivo consequence of R265Q not established\", \"Mechanism by which R265Q enhances ERα binding unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-transcriptional control of PPARGC1B and a requirement for it in adipogenesis, defining an upstream regulatory layer.\",\n      \"evidence\": \"ZFP36L1 knockdown/overexpression, 3'-UTR AU-rich element analysis, and PPARGC1B knockdown in MSC adipogenesis assays\",\n      \"pmids\": [\"29993187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZFP36L1–3'UTR binding shown indirectly\", \"Coactivation targets driving adipogenesis not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a causal, dose-dependent role for PPARGC1B in brown adipocyte mitochondrial function and lipolysis using allelic editing of a cis-regulatory variant.\",\n      \"evidence\": \"Scarless CRISPR/Cas9 editing of rs10071329 in a human brown adipocyte line with expression, respiration, and lipolysis readouts\",\n      \"pmids\": [\"38190589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor mediating the cis-eQTL effect not identified\", \"In vivo metabolic consequence in humans not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide direct target genes of PPARGC1B coactivation and how its activity is integrated across hepatic versus adipose tissues remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ChIP/genomic target map in the corpus\", \"Tissue-specific receptor partners beyond ERα/ERRγ uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ESR1\", \"ESRRG\", \"ZFP36L1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}