{"gene":"CEBPG","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1990,"finding":"Ig/EBP-1 (CEBPG) is a basic-leucine zipper protein that binds specifically to E sites in the IgH enhancer and VH1 promoter, as well as to C/EBP binding sites in the RSV LTR and murine albumin promoter. CEBPG heterodimerizes with C/EBP through its leucine repeat region, making it the first C/EBP family member shown to form heterodimers with C/EBP.","method":"Fusion protein DNA-binding assay, sequence analysis, heterodimerization assay (leucine zipper region)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical binding assays, sequence-based domain identification, heterodimerization demonstrated experimentally, replicated conceptually by subsequent papers","pmids":["2121606"],"is_preprint":false},{"year":1991,"finding":"GPE1-BP (CEBPG) binds specifically to GPE1, a cis-acting element of the G-CSF gene promoter that functions as an LPS-inducible element; nuclear extract from COS cells transfected with the cDNA showed GPE1-binding activity.","method":"cDNA cloning, transfection of COS cells, nuclear extract DNA-binding assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA-binding assay in transfected cells, single lab, two orthogonal approaches (cloning + functional binding)","pmids":["1709121"],"is_preprint":false},{"year":2007,"finding":"CEBPG transcriptionally upregulates ERCC5/XPG expression by binding to a recognition site in the ERCC5 5' regulatory region; this regulation is modified by E2F1 and YY1, which bind adjacent sites on sense and antisense strands respectively. CEBPG, E2F1, and YY1 binding to their respective sites was confirmed by EMSA.","method":"Expression vector transfection, luciferase reporter assay, electrophoretic mobility shift assay (EMSA)","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus EMSA in two cell lines, single lab, two orthogonal methods","pmids":["17893230"],"is_preprint":false},{"year":2020,"finding":"CEBPG activates the PI3K-AKT signaling pathway in esophageal squamous cell carcinoma by directly binding to distal enhancers and/or promoters of pathway genes including CCND1, MYC, and CDK2, promoting cell proliferation and migration.","method":"ChIP-seq, in vitro proliferation/migration assays, in vivo mouse model, knockdown/overexpression","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq demonstrates direct binding, functional assays in vitro and in vivo, single lab","pmids":["33163273"],"is_preprint":false},{"year":2021,"finding":"CEBPG promotes AML cell proliferation by transcriptionally activating EIF4EBP1 (a known repressor of translation); knockdown of EIF4EBP1 downstream of CEBPG reduced AML cell growth, placing CEBPG upstream of EIF4EBP1 in AML progression.","method":"shRNA knockdown, RNA-seq, ChIP-seq (public data), CCK-8 proliferation assay, western blotting, flow cytometry","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via sequential knockdown, RNA-seq, and ChIP-seq data, single lab","pmids":["34743716"],"is_preprint":false},{"year":2023,"finding":"CEBPG suppresses ferroptosis in ovarian cancer cells by directly binding to the promoter of SLC7A11 (a key ferroptosis regulator) and transcriptionally activating its expression, as demonstrated by CUT&Tag and dual luciferase reporter assays.","method":"CUT&Tag chromatin profiling, dual luciferase reporter assay, RNA-seq, knockdown, in vivo orthotopic mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin occupancy (CUT&Tag) plus reporter assay, single lab, two orthogonal methods","pmids":["37210575"],"is_preprint":false},{"year":2025,"finding":"ATF4 forms a heterodimer with CEBPG, and this heterodimer transcriptionally upregulates RETREG1 (reticulophagy regulator 1) by binding to identified sites in its promoter and enhancer regions, activating reticulophagy to protect against lipotoxicity.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), knockdown experiments, in vitro and in vivo mouse models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP identifies heterodimer and binding sites, single lab, two orthogonal methods","pmids":["40437698"],"is_preprint":false},{"year":2026,"finding":"CEBPG regulates transcription of ERN1 and TMBIM6 in cancer-associated fibroblasts in an enhancer-associated manner; disruption of the CEBPG-IRE1α/TMBIM6 axis attenuated myoCAF properties and abrogated palmitic acid-driven metastasis of oral squamous cell carcinoma.","method":"Chromatin landscape analysis (H3K27ac ChIP), enhancer-associated transcription assays, knockdown, in vivo orthotopic tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin occupancy and functional knockdown in vitro and in vivo, single lab","pmids":["42227941"],"is_preprint":false},{"year":2025,"finding":"In CD8+ T cells under nutrient stress, ATF4 and CEBPG jointly establish an adaptive metabolic program that promotes amino acid synthesis and uptake while maintaining mitochondrial anaplerosis, preventing failure of central carbon metabolism.","method":"Gene-regulatory and metabolic network analysis in CD8+ T cells under nutrient stress (transcriptional and metabolic profiling)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic pathway placement inferred from transcriptional/metabolic profiling without direct protein-level binding or mutagenesis data described in abstract","pmids":["bio_10.1101_2025.01.22.632829"],"is_preprint":true}],"current_model":"CEBPG (Ig/EBP-1/GPE1-BP) is a ubiquitously expressed basic-leucine zipper transcription factor that homodimerizes and heterodimerizes with C/EBP family members (including ATF4) to bind CCAAT/enhancer elements in gene promoters and enhancers, directly regulating targets involved in DNA repair (ERCC5), ferroptosis resistance (SLC7A11), reticulophagy (RETREG1), ER stress adaptation (ERN1, TMBIM6), and proliferative signaling (EIF4EBP1, PI3K-AKT pathway genes), thereby acting as a context-dependent transcriptional activator in both normal cellular stress responses and cancer progression."},"narrative":{"mechanistic_narrative":"CEBPG (Ig/EBP-1, GPE1-BP) is a basic-leucine zipper transcription factor that recognizes CCAAT/enhancer-type DNA elements and functions as a context-dependent transcriptional activator across stress-response and cancer programs [PMID:2121606, PMID:33163273]. It was the first C/EBP family member shown to heterodimerize with C/EBP through its leucine-repeat region, and it binds E sites in immunoglobulin enhancer/promoter elements as well as C/EBP sites in viral and hepatic promoters [PMID:2121606]; it also recognizes the LPS-inducible GPE1 element of the G-CSF promoter [PMID:1709121]. Through direct promoter and enhancer occupancy, CEBPG drives diverse target genes: it upregulates the DNA-repair nuclease ERCC5/XPG in concert with adjacent E2F1 and YY1 binding [PMID:17893230], activates PI3K-AKT proliferative genes (CCND1, MYC, CDK2) in esophageal squamous carcinoma [PMID:33163273], and induces the translational regulator EIF4EBP1 to promote AML proliferation [PMID:34743716]. In stress-adaptation programs CEBPG partners with ATF4: the ATF4-CEBPG heterodimer transactivates RETREG1 to activate reticulophagy and protect against lipotoxicity [PMID:40437698], and CEBPG also regulates the ER-stress genes ERN1 and TMBIM6 via enhancer-associated transcription in cancer-associated fibroblasts to support metastasis [PMID:42227941]. It additionally suppresses ferroptosis by transactivating SLC7A11 [PMID:37210575]. No structural model of CEBPG-DNA or CEBPG-heterodimer complexes is characterized in the available corpus.","teleology":[{"year":1990,"claim":"Established CEBPG as a bZIP DNA-binding protein and the first C/EBP family member capable of heterodimerization, defining its core biochemical mode of action.","evidence":"Fusion-protein DNA-binding assays and leucine-zipper heterodimerization assays on IgH enhancer, VH1 promoter, RSV LTR and albumin promoter elements","pmids":["2121606"],"confidence":"High","gaps":["No genome-wide target map at this stage","Functional consequence of heterodimerization on transcription not yet shown","No structural resolution of the dimer interface"]},{"year":1991,"claim":"Identified a physiological DNA target by showing CEBPG binds the LPS-inducible GPE1 element of the G-CSF promoter, linking it to inducible inflammatory gene expression.","evidence":"cDNA cloning, COS cell transfection and nuclear-extract DNA-binding assay","pmids":["1709121"],"confidence":"Medium","gaps":["Transcriptional activation of endogenous G-CSF not demonstrated","Single lab","Dimer partner at GPE1 not defined"]},{"year":2007,"claim":"Demonstrated CEBPG functions as a direct transcriptional regulator of a DNA-repair gene, showing it activates ERCC5/XPG within a combinatorial promoter context.","evidence":"Luciferase reporter assays and EMSA in two cell lines with E2F1 and YY1 co-occupancy","pmids":["17893230"],"confidence":"Medium","gaps":["Cellular DNA-repair phenotype of CEBPG loss not tested","Interplay logic with E2F1/YY1 not mechanistically resolved","No in vivo validation"]},{"year":2020,"claim":"Placed CEBPG as a driver of proliferative signaling in cancer by mapping its direct enhancer/promoter binding to PI3K-AKT pathway genes.","evidence":"ChIP-seq plus in vitro proliferation/migration and in vivo mouse models with knockdown/overexpression in esophageal squamous cell carcinoma","pmids":["33163273"],"confidence":"Medium","gaps":["Direct activation of each named target not individually validated by reporter","Dimer partner in this context unknown","Single lab"]},{"year":2021,"claim":"Defined a CEBPG transcriptional axis in AML by placing it upstream of EIF4EBP1 through epistatic knockdown.","evidence":"shRNA knockdown, RNA-seq, public ChIP-seq, proliferation and flow cytometry assays","pmids":["34743716"],"confidence":"Medium","gaps":["Direct CEBPG occupancy at EIF4EBP1 used public data rather than primary ChIP","Translational-control mechanism downstream not dissected","Single lab"]},{"year":2023,"claim":"Linked CEBPG to ferroptosis resistance by showing direct transactivation of SLC7A11, extending its role into metabolic cell-death control.","evidence":"CUT&Tag chromatin profiling, dual luciferase reporter, RNA-seq, knockdown and orthotopic ovarian cancer model","pmids":["37210575"],"confidence":"Medium","gaps":["Upstream signals controlling CEBPG in this context unknown","Dimer partner not identified","Single lab"]},{"year":2025,"claim":"Identified the ATF4-CEBPG heterodimer as a specific transactivator of RETREG1, connecting the factor to reticulophagy-mediated protection from lipotoxicity.","evidence":"Reciprocal Co-IP, ChIP at promoter/enhancer sites, knockdown, and in vitro/in vivo mouse models","pmids":["40437698"],"confidence":"Medium","gaps":["Relative contribution of CEBPG homodimer vs ATF4 heterodimer not quantified","Stoichiometry of the heterodimer not resolved","Single lab"]},{"year":2025,"claim":"Proposed that ATF4 and CEBPG jointly establish an adaptive metabolic program in nutrient-stressed CD8+ T cells, suggesting a role in immune-cell metabolic resilience.","evidence":"Gene-regulatory and metabolic network analysis in CD8+ T cells under nutrient stress (preprint)","pmids":["bio_10.1101_2025.01.22.632829"],"confidence":"Low","gaps":["Preprint without direct protein-level binding or mutagenesis data","Direct target genes not defined","Causality vs correlation in network inference unresolved"]},{"year":2026,"claim":"Extended CEBPG into the tumor microenvironment by showing enhancer-associated regulation of ER-stress genes ERN1 and TMBIM6 that drives cancer-associated fibroblast phenotypes and metastasis.","evidence":"H3K27ac ChIP chromatin landscape analysis, enhancer-associated transcription assays, knockdown and orthotopic oral squamous cell carcinoma models","pmids":["42227941"],"confidence":"Medium","gaps":["Direct CEBPG binding at ERN1/TMBIM6 enhancers vs broader chromatin state not fully separated","Signal that activates CEBPG in CAFs unknown","Single lab"]},{"year":null,"claim":"How CEBPG dimer-partner choice (homodimer vs C/EBP vs ATF4) is regulated to select among its diverse target programs across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CEBPG-DNA or heterodimer complexes","Determinants of context-specific target selection unknown","Upstream signaling controlling CEBPG activity across contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,5,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3,5,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["ATF4","E2F1","YY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53567","full_name":"CCAAT/enhancer-binding protein gamma","aliases":[],"length_aa":150,"mass_kda":16.4,"function":"Transcription factor that binds to the promoter and the enhancer regions of target genes. Binds to the enhancer element PRE-I (positive regulatory element-I) of the IL-4 gene (PubMed:7665092). Binds to the promoter and the enhancer of the immunoglobulin heavy chain. Binds to GPE1, a cis-acting element in the G-CSF gene promoter","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P53567/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEBPG","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEBPG","total_profiled":1310},"omim":[{"mim_id":"605180","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 2; SLC38A2","url":"https://www.omim.org/entry/605180"},{"mim_id":"138972","title":"CCAAT/ENHANCER-BINDING PROTEIN, GAMMA; CEBPG","url":"https://www.omim.org/entry/138972"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEBPG"},"hgnc":{"alias_symbol":["GPE1BP","IG/EBP-1"],"prev_symbol":[]},"alphafold":{"accession":"P53567","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53567","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53567-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53567-F1-predicted_aligned_error_v6.png","plddt_mean":74.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEBPG","jax_strain_url":"https://www.jax.org/strain/search?query=CEBPG"},"sequence":{"accession":"P53567","fasta_url":"https://rest.uniprot.org/uniprotkb/P53567.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53567/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53567"}},"corpus_meta":[{"pmid":"2121606","id":"PMC_2121606","title":"Ig/EBP-1: a ubiquitously expressed immunoglobulin enhancer binding protein that is similar to C/EBP and heterodimerizes with C/EBP.","date":"1990","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/2121606","citation_count":254,"is_preprint":false},{"pmid":"37210575","id":"PMC_37210575","title":"CEBPG suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancer.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37210575","citation_count":38,"is_preprint":false},{"pmid":"1709121","id":"PMC_1709121","title":"Molecular cloning of cDNA and a chromosomal gene encoding GPE1-BP, a nuclear protein which binds to granulocyte colony-stimulating factor promoter element 1.","date":"1991","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/1709121","citation_count":37,"is_preprint":false},{"pmid":"17893230","id":"PMC_17893230","title":"CEBPG regulates ERCC5/XPG expression in human bronchial epithelial cells and this regulation is modified by E2F1/YY1 interactions.","date":"2007","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17893230","citation_count":33,"is_preprint":false},{"pmid":"16255782","id":"PMC_16255782","title":"CEBPG transcription factor correlates with antioxidant and DNA repair genes in normal bronchial epithelial cells but not in individuals with bronchogenic carcinoma.","date":"2005","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16255782","citation_count":31,"is_preprint":false},{"pmid":"33163273","id":"PMC_33163273","title":"CEBPG promotes esophageal squamous cell carcinoma progression by enhancing PI3K-AKT signaling.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33163273","citation_count":29,"is_preprint":false},{"pmid":"34743716","id":"PMC_34743716","title":"CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34743716","citation_count":11,"is_preprint":false},{"pmid":"23888109","id":"PMC_23888109","title":"CEBPG Exhibits Allele-Specific Expression in Human Bronchial Epithelial Cells.","date":"2013","source":"Gene regulation and systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/23888109","citation_count":10,"is_preprint":false},{"pmid":"40437698","id":"PMC_40437698","title":"RETREG1-mediated reticulophagy is activated by an ATF4-CEBPG/C/EBPγ heterodimer and confers protection against lipotoxicity.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40437698","citation_count":4,"is_preprint":false},{"pmid":"34010702","id":"PMC_34010702","title":"Interacting C/EBPg and YBP regulate DNA methyltransferase 1 expression in Bombyx mori embryos and ovaries.","date":"2021","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34010702","citation_count":3,"is_preprint":false},{"pmid":"42227941","id":"PMC_42227941","title":"CEBPG-Mediated Palmitic Acid Adaptation of Cancer-Associated Fibroblasts Drives Metastasis of Oral Squamous Cell Carcinoma.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42227941","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.22.632829","title":"Biosynthetic plasticity enables CD8+ T cell functional resilience under nutrient stress","date":"2025-01-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.22.632829","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8988,"output_tokens":2181,"usd":0.02984,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9212,"output_tokens":3159,"usd":0.062518,"stage2_stop_reason":"end_turn"},"total_usd":0.092358,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Ig/EBP-1 (CEBPG) is a basic-leucine zipper protein that binds specifically to E sites in the IgH enhancer and VH1 promoter, as well as to C/EBP binding sites in the RSV LTR and murine albumin promoter. CEBPG heterodimerizes with C/EBP through its leucine repeat region, making it the first C/EBP family member shown to form heterodimers with C/EBP.\",\n      \"method\": \"Fusion protein DNA-binding assay, sequence analysis, heterodimerization assay (leucine zipper region)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical binding assays, sequence-based domain identification, heterodimerization demonstrated experimentally, replicated conceptually by subsequent papers\",\n      \"pmids\": [\"2121606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"GPE1-BP (CEBPG) binds specifically to GPE1, a cis-acting element of the G-CSF gene promoter that functions as an LPS-inducible element; nuclear extract from COS cells transfected with the cDNA showed GPE1-binding activity.\",\n      \"method\": \"cDNA cloning, transfection of COS cells, nuclear extract DNA-binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA-binding assay in transfected cells, single lab, two orthogonal approaches (cloning + functional binding)\",\n      \"pmids\": [\"1709121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEBPG transcriptionally upregulates ERCC5/XPG expression by binding to a recognition site in the ERCC5 5' regulatory region; this regulation is modified by E2F1 and YY1, which bind adjacent sites on sense and antisense strands respectively. CEBPG, E2F1, and YY1 binding to their respective sites was confirmed by EMSA.\",\n      \"method\": \"Expression vector transfection, luciferase reporter assay, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus EMSA in two cell lines, single lab, two orthogonal methods\",\n      \"pmids\": [\"17893230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CEBPG activates the PI3K-AKT signaling pathway in esophageal squamous cell carcinoma by directly binding to distal enhancers and/or promoters of pathway genes including CCND1, MYC, and CDK2, promoting cell proliferation and migration.\",\n      \"method\": \"ChIP-seq, in vitro proliferation/migration assays, in vivo mouse model, knockdown/overexpression\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq demonstrates direct binding, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"33163273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEBPG promotes AML cell proliferation by transcriptionally activating EIF4EBP1 (a known repressor of translation); knockdown of EIF4EBP1 downstream of CEBPG reduced AML cell growth, placing CEBPG upstream of EIF4EBP1 in AML progression.\",\n      \"method\": \"shRNA knockdown, RNA-seq, ChIP-seq (public data), CCK-8 proliferation assay, western blotting, flow cytometry\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via sequential knockdown, RNA-seq, and ChIP-seq data, single lab\",\n      \"pmids\": [\"34743716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEBPG suppresses ferroptosis in ovarian cancer cells by directly binding to the promoter of SLC7A11 (a key ferroptosis regulator) and transcriptionally activating its expression, as demonstrated by CUT&Tag and dual luciferase reporter assays.\",\n      \"method\": \"CUT&Tag chromatin profiling, dual luciferase reporter assay, RNA-seq, knockdown, in vivo orthotopic mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin occupancy (CUT&Tag) plus reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"37210575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4 forms a heterodimer with CEBPG, and this heterodimer transcriptionally upregulates RETREG1 (reticulophagy regulator 1) by binding to identified sites in its promoter and enhancer regions, activating reticulophagy to protect against lipotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), knockdown experiments, in vitro and in vivo mouse models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP identifies heterodimer and binding sites, single lab, two orthogonal methods\",\n      \"pmids\": [\"40437698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CEBPG regulates transcription of ERN1 and TMBIM6 in cancer-associated fibroblasts in an enhancer-associated manner; disruption of the CEBPG-IRE1α/TMBIM6 axis attenuated myoCAF properties and abrogated palmitic acid-driven metastasis of oral squamous cell carcinoma.\",\n      \"method\": \"Chromatin landscape analysis (H3K27ac ChIP), enhancer-associated transcription assays, knockdown, in vivo orthotopic tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin occupancy and functional knockdown in vitro and in vivo, single lab\",\n      \"pmids\": [\"42227941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In CD8+ T cells under nutrient stress, ATF4 and CEBPG jointly establish an adaptive metabolic program that promotes amino acid synthesis and uptake while maintaining mitochondrial anaplerosis, preventing failure of central carbon metabolism.\",\n      \"method\": \"Gene-regulatory and metabolic network analysis in CD8+ T cells under nutrient stress (transcriptional and metabolic profiling)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic pathway placement inferred from transcriptional/metabolic profiling without direct protein-level binding or mutagenesis data described in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.01.22.632829\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CEBPG (Ig/EBP-1/GPE1-BP) is a ubiquitously expressed basic-leucine zipper transcription factor that homodimerizes and heterodimerizes with C/EBP family members (including ATF4) to bind CCAAT/enhancer elements in gene promoters and enhancers, directly regulating targets involved in DNA repair (ERCC5), ferroptosis resistance (SLC7A11), reticulophagy (RETREG1), ER stress adaptation (ERN1, TMBIM6), and proliferative signaling (EIF4EBP1, PI3K-AKT pathway genes), thereby acting as a context-dependent transcriptional activator in both normal cellular stress responses and cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEBPG (Ig/EBP-1, GPE1-BP) is a basic-leucine zipper transcription factor that recognizes CCAAT/enhancer-type DNA elements and functions as a context-dependent transcriptional activator across stress-response and cancer programs [#0, #3]. It was the first C/EBP family member shown to heterodimerize with C/EBP through its leucine-repeat region, and it binds E sites in immunoglobulin enhancer/promoter elements as well as C/EBP sites in viral and hepatic promoters [#0]; it also recognizes the LPS-inducible GPE1 element of the G-CSF promoter [#1]. Through direct promoter and enhancer occupancy, CEBPG drives diverse target genes: it upregulates the DNA-repair nuclease ERCC5/XPG in concert with adjacent E2F1 and YY1 binding [#2], activates PI3K-AKT proliferative genes (CCND1, MYC, CDK2) in esophageal squamous carcinoma [#3], and induces the translational regulator EIF4EBP1 to promote AML proliferation [#4]. In stress-adaptation programs CEBPG partners with ATF4: the ATF4-CEBPG heterodimer transactivates RETREG1 to activate reticulophagy and protect against lipotoxicity [#6], and CEBPG also regulates the ER-stress genes ERN1 and TMBIM6 via enhancer-associated transcription in cancer-associated fibroblasts to support metastasis [#7]. It additionally suppresses ferroptosis by transactivating SLC7A11 [#5]. No structural model of CEBPG-DNA or CEBPG-heterodimer complexes is characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established CEBPG as a bZIP DNA-binding protein and the first C/EBP family member capable of heterodimerization, defining its core biochemical mode of action.\",\n      \"evidence\": \"Fusion-protein DNA-binding assays and leucine-zipper heterodimerization assays on IgH enhancer, VH1 promoter, RSV LTR and albumin promoter elements\",\n      \"pmids\": [\"2121606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide target map at this stage\", \"Functional consequence of heterodimerization on transcription not yet shown\", \"No structural resolution of the dimer interface\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identified a physiological DNA target by showing CEBPG binds the LPS-inducible GPE1 element of the G-CSF promoter, linking it to inducible inflammatory gene expression.\",\n      \"evidence\": \"cDNA cloning, COS cell transfection and nuclear-extract DNA-binding assay\",\n      \"pmids\": [\"1709121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional activation of endogenous G-CSF not demonstrated\", \"Single lab\", \"Dimer partner at GPE1 not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated CEBPG functions as a direct transcriptional regulator of a DNA-repair gene, showing it activates ERCC5/XPG within a combinatorial promoter context.\",\n      \"evidence\": \"Luciferase reporter assays and EMSA in two cell lines with E2F1 and YY1 co-occupancy\",\n      \"pmids\": [\"17893230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular DNA-repair phenotype of CEBPG loss not tested\", \"Interplay logic with E2F1/YY1 not mechanistically resolved\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CEBPG as a driver of proliferative signaling in cancer by mapping its direct enhancer/promoter binding to PI3K-AKT pathway genes.\",\n      \"evidence\": \"ChIP-seq plus in vitro proliferation/migration and in vivo mouse models with knockdown/overexpression in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"33163273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct activation of each named target not individually validated by reporter\", \"Dimer partner in this context unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a CEBPG transcriptional axis in AML by placing it upstream of EIF4EBP1 through epistatic knockdown.\",\n      \"evidence\": \"shRNA knockdown, RNA-seq, public ChIP-seq, proliferation and flow cytometry assays\",\n      \"pmids\": [\"34743716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPG occupancy at EIF4EBP1 used public data rather than primary ChIP\", \"Translational-control mechanism downstream not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CEBPG to ferroptosis resistance by showing direct transactivation of SLC7A11, extending its role into metabolic cell-death control.\",\n      \"evidence\": \"CUT&Tag chromatin profiling, dual luciferase reporter, RNA-seq, knockdown and orthotopic ovarian cancer model\",\n      \"pmids\": [\"37210575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals controlling CEBPG in this context unknown\", \"Dimer partner not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the ATF4-CEBPG heterodimer as a specific transactivator of RETREG1, connecting the factor to reticulophagy-mediated protection from lipotoxicity.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at promoter/enhancer sites, knockdown, and in vitro/in vivo mouse models\",\n      \"pmids\": [\"40437698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of CEBPG homodimer vs ATF4 heterodimer not quantified\", \"Stoichiometry of the heterodimer not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that ATF4 and CEBPG jointly establish an adaptive metabolic program in nutrient-stressed CD8+ T cells, suggesting a role in immune-cell metabolic resilience.\",\n      \"evidence\": \"Gene-regulatory and metabolic network analysis in CD8+ T cells under nutrient stress (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.22.632829\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint without direct protein-level binding or mutagenesis data\", \"Direct target genes not defined\", \"Causality vs correlation in network inference unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended CEBPG into the tumor microenvironment by showing enhancer-associated regulation of ER-stress genes ERN1 and TMBIM6 that drives cancer-associated fibroblast phenotypes and metastasis.\",\n      \"evidence\": \"H3K27ac ChIP chromatin landscape analysis, enhancer-associated transcription assays, knockdown and orthotopic oral squamous cell carcinoma models\",\n      \"pmids\": [\"42227941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPG binding at ERN1/TMBIM6 enhancers vs broader chromatin state not fully separated\", \"Signal that activates CEBPG in CAFs unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEBPG dimer-partner choice (homodimer vs C/EBP vs ATF4) is regulated to select among its diverse target programs across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CEBPG-DNA or heterodimer complexes\", \"Determinants of context-specific target selection unknown\", \"Upstream signaling controlling CEBPG activity across contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATF4\", \"E2F1\", \"YY1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}