{"gene":"EID1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"EID1 (C15orf3) encodes a novel human protein of 187 amino acids (predicted 20.8 kDa) located on chromosome 15q21.1→q21.2, with ubiquitous expression in adult tissues and conserved homologs in rat and mouse.","method":"cDNA cloning, Northern blot, radiation hybrid mapping","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct molecular characterization of the gene/protein, single lab, single study","pmids":["10828624"],"is_preprint":false},{"year":2008,"finding":"EID-1 inhibits transcriptional activation of MyoD-responsive promoters required for myogenic differentiation; necdin interacts with EID-1 (identified by cytoplasmic two-hybrid screen), relieves EID-1-dependent repression of myogenic promoters, extends the half-life of EID-1, and relocalizes EID-1 from the nucleus to the cytoplasm when co-expressed.","method":"Yeast two-hybrid screen, transactivation assay, co-expression in transfected cells, pulse-chase half-life measurement, subcellular localization imaging","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (two-hybrid, transactivation assay, localization), single lab","pmids":["18557765"],"is_preprint":false},{"year":2007,"finding":"EID-1 interacts with the AF-2 domain of the orphan nuclear receptor SF-1, competes with coactivator SRC-1, and represses SF-1 transactivation but not LRH-1, ERRγ, or mCAR transactivation; EID-1 colocalizes with SF-1 in mammalian cells.","method":"Yeast two-hybrid, GST pull-down, transient transfection transactivation assay, colocalization imaging","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays (Y2H + GST pull-down) plus functional transactivation assay, single lab","pmids":["18182853"],"is_preprint":false},{"year":2011,"finding":"EID1 nuclear translocation is increased in cortical neurons of Alzheimer's disease patient brains; overexpression of EID1 in transgenic mice leads to increased nuclear localization in neurons, disrupted neurofilament organization, astrogliosis, reduced hippocampal long-term potentiation, and impaired spatial learning and memory, likely through inhibition of CBP/p300-mediated histone and p53 acetylation.","method":"Immunofluorescence/immunohistochemistry in human AD brains and transgenic mice, LTP electrophysiology, spatial memory behavioral assays, transgenic mouse generation","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo methods (transgenic mouse, electrophysiology, behavior), single lab","pmids":["22186421"],"is_preprint":false},{"year":2014,"finding":"EID1 directly interacts with SHP (NR0B2) and E2F1 proteins (confirmed by GST pull-down); EID1 and SHP associate with the Egr-1 promoter (confirmed by chromatin immunoprecipitation) and together repress E2F1-mediated Egr-1 transactivation in hepatoma and stellate cells.","method":"GST pull-down, chromatin immunoprecipitation (ChIP), transient transfection/reporter assay","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction (GST pull-down) plus ChIP and functional reporter assay, single lab","pmids":["24619556"],"is_preprint":false},{"year":2014,"finding":"Pcid2 associates with EID1 and is present in the CBP/p300-EID1 complex in embryonic stem cells; MDM2 is identified as an E3 ligase mediating K48-linked ubiquitination and proteasomal degradation of EID1; Pcid2 binding to EID1 blocks MDM2 association, thereby stabilizing EID1 and sustaining inhibition of CBP/p300 HAT activity to suppress developmental gene expression.","method":"Co-immunoprecipitation, ubiquitylation assay (K48-linkage), genetic KO of Pcid2 in mouse and human ESCs","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying complex members plus in-cell ubiquitylation assay and genetic KO, single lab","pmids":["24167073"],"is_preprint":false},{"year":2015,"finding":"EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation; the SCF(FBXO21) ubiquitin ligase complex, using FBXO21 as substrate-recognition subunit, polyubiquitylates EID1 both in vitro and in vivo and is required for efficient EID1 degradation in cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma protein-binding domain.","method":"In vitro ubiquitylation assay, in vivo co-immunoprecipitation, degron mutagenesis, proteasome inhibitor experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted ubiquitylation assay plus in vivo validation plus mutagenesis of degron, replicated by independent lab (PMID 26085330)","pmids":["26631746","26085330"],"is_preprint":false},{"year":2015,"finding":"FBXO21 (central and C-terminal portion) interacts with the C-terminal region of EID1 in transfected cells; FBXO21 overexpression downregulates EID1, FBXO21 gene disruption (CRISPR/Cas9) stabilizes EID1 and causes its accumulation in cytoplasm and nucleus; in vitro ubiquitylation assay confirms EID1 is a direct substrate of SCF(FBXO21).","method":"Co-immunoprecipitation in transfected cells, CRISPR/Cas9 gene disruption, in vitro ubiquitylation assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation reconstitution plus genetic KO plus interaction mapping, consistent with independent lab (PMID 26631746)","pmids":["26085330"],"is_preprint":false},{"year":2015,"finding":"Palmitoylation modifies EID1; this modification regulates EID1 protein degradation and CBP/p300 histone acetyltransferase activity at the switch between self-renewal and differentiation of neural stem cells.","method":"Palmitoylation inhibitor (2-bromopalmitate) treatment, functional assays of NSC differentiation and cell cycle exit, HAT activity assay","journal":"Molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — palmitoylation modification inferred from inhibitor treatment rather than direct acylation assay or mutagenesis; single lab, indirect evidence","pmids":["26497028"],"is_preprint":false},{"year":2010,"finding":"EID1 overexpression in 3T3-L1 preadipocytes reduces PPARγ ligand-dependent transactivation, decreases triglyceride stores, and increases expression of UCP1 and PGC-1α (brown fat markers); EID1 binds to pRB at the onset of adipocyte differentiation and may act to reduce pRB levels.","method":"Overexpression in 3T3-L1 cells, transactivation assay, co-immunoprecipitation (EID1-pRB binding), gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for pRB interaction, functional assays without mechanistic pathway reconstitution, single lab","pmids":["20541531"],"is_preprint":false},{"year":2010,"finding":"miR-138 directly targets the 3' UTR of EID1 mRNA (validated by luciferase reporter assay) and negatively regulates EID1 expression; knockdown of EID1 by RNA interference inhibits adipocyte differentiation of human adipose-derived mesenchymal stem cells.","method":"Luciferase reporter assay, siRNA knockdown, adipogenic differentiation assay","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter validation plus loss-of-function (siRNA) with defined cellular phenotype, single lab","pmids":["20486779"],"is_preprint":false},{"year":2019,"finding":"EID1 knockout in mice reduces neural stem cell (NSC) proliferation and neurosphere formation; loss of EID1 attenuates PI3K/AKT/GSK3β signaling pathway activity in NSCs, and EID1-KO mice show poorer learning and memory and smaller neonatal telencephalon volume.","method":"Knockout mouse generation, NSC isolation, neurosphere assay, CCK-8 proliferation assay, Western blotting of PI3K/AKT/GSK3β pathway components, behavioral testing","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts and pathway analysis, single lab","pmids":["30926163"],"is_preprint":false},{"year":2020,"finding":"EID1 localizes to the nucleus of preadipocytes in speckles and binds to the promoter sequence of glycerol-3-phosphate dehydrogenase (GPDH); EID1 overexpression during adipocyte differentiation downregulates GPDH expression and inhibits lipid accumulation in 3T3-L1 cells.","method":"Confocal microscopy (nuclear localization), ChIP (EID1 binding to GPDH promoter), DNA microarray, overexpression in 3T3-L1 cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for promoter binding plus subcellular localization and functional overexpression phenotype, single lab","pmids":["32056205"],"is_preprint":false}],"current_model":"EID1 is a short-lived nuclear protein that inhibits CBP/p300 histone acetyltransferase activity and represses the transcription of differentiation-promoting genes; its abundance is tightly controlled by the SCF(FBXO21) E3 ubiquitin ligase complex, which recognizes a peptidic degron overlapping the retinoblastoma protein-binding domain and mediates polyubiquitylation and proteasomal degradation of EID1, while binding partners such as Pcid2 or necdin can stabilize EID1 by blocking this degradation pathway or relocalizing it from the nucleus."},"narrative":{"mechanistic_narrative":"EID1 is a short-lived, ubiquitously expressed nuclear protein that functions as a transcriptional corepressor by inhibiting CBP/p300 histone acetyltransferase activity and thereby restraining differentiation- and developmental-gene programs [PMID:10828624, PMID:24167073]. It represses transactivation by multiple sequence-specific factors, including MyoD-responsive myogenic promoters [PMID:18557765], the orphan nuclear receptor SF-1—where it competes with the coactivator SRC-1 [PMID:18182853]—and E2F1 at the Egr-1 promoter in concert with SHP/NR0B2 [PMID:24619556]; EID1 also binds the retinoblastoma protein (pRB) [PMID:20541531] and occupies target promoters directly, as shown for the GPDH promoter in adipocytes [PMID:32056205]. Through these activities EID1 acts as a brake on lineage commitment: it suppresses adipogenic and brown-fat gene programs [PMID:20541531, PMID:32056205], yet is itself required for adipocyte differentiation of mesenchymal stem cells and for neural stem cell proliferation, where its loss attenuates PI3K/AKT/GSK3β signaling and impairs learning and memory [PMID:20486779, PMID:30926163]. EID1 abundance is the dominant control point: it carries a modular peptidic degron overlapping its pRB-binding domain that is recognized by the SCF(FBXO21) ubiquitin ligase for polyubiquitylation and proteasomal degradation [PMID:26631746, PMID:26085330], with MDM2 additionally mediating K48-linked ubiquitination [PMID:24167073]; binding partners counteract this turnover, as necdin stabilizes EID1 and relocalizes it to the cytoplasm [PMID:18557765] and Pcid2 blocks MDM2 association to sustain CBP/p300 inhibition in embryonic stem cells [PMID:24167073]. Excess nuclear EID1 is pathologically relevant: it accumulates in cortical neurons of Alzheimer's disease brains, and its overexpression in mice disrupts neurofilament organization, reduces long-term potentiation, and impairs spatial memory, consistent with loss of CBP/p300-mediated histone and p53 acetylation [PMID:22186421].","teleology":[{"year":2000,"claim":"Establishing the gene's existence and basic features defined EID1 as a conserved, ubiquitously expressed human protein available for functional study.","evidence":"cDNA cloning, Northern blot, and radiation hybrid mapping of the 187-aa protein","pmids":["10828624"],"confidence":"Medium","gaps":["No molecular function assigned at cloning","No subcellular localization or interaction partners defined"]},{"year":2007,"claim":"Identifying EID1 as a corepressor of the nuclear receptor SF-1 that competes with SRC-1 established a coactivator-displacement mechanism for its transcriptional repression.","evidence":"Yeast two-hybrid, GST pull-down, and transactivation/colocalization assays in mammalian cells","pmids":["18182853"],"confidence":"Medium","gaps":["Selectivity for SF-1 over related receptors not mechanistically explained","Did not link repression to CBP/p300 inhibition directly"]},{"year":2008,"claim":"Showing EID-1 inhibits MyoD-responsive myogenic promoters and is regulated by necdin connected EID1 repression to a differentiation program and to partner-controlled stability and localization.","evidence":"Yeast two-hybrid, transactivation assays, pulse-chase half-life, and subcellular localization in transfected cells","pmids":["18557765"],"confidence":"Medium","gaps":["Mechanism of necdin-driven nuclear-to-cytoplasmic relocalization unresolved","How relocalization relieves repression not biochemically defined"]},{"year":2010,"claim":"Defining EID1 as both a repressor of PPARγ/brown-fat programs and a pRB-binding, miR-138-regulated, differentiation-required factor placed EID1 at a node controlling adipogenic commitment.","evidence":"3T3-L1 overexpression with transactivation and Co-IP assays; luciferase 3'UTR validation and siRNA knockdown in adipose-derived MSCs","pmids":["20541531","20486779"],"confidence":"Medium","gaps":["Apparent opposing roles (represses PPARγ yet required for differentiation) not reconciled","pRB interaction rests on a single Co-IP","Direct promoter occupancy not yet shown at this stage"]},{"year":2011,"claim":"Linking nuclear EID1 accumulation to Alzheimer's pathology and to in vivo synaptic and cognitive deficits established a disease-relevant consequence of CBP/p300 inhibition.","evidence":"Immunostaining of human AD brains, transgenic mouse overexpression, LTP electrophysiology, and spatial memory testing","pmids":["22186421"],"confidence":"Medium","gaps":["Causal contribution of CBP/p300 inhibition inferred rather than directly demonstrated","Trigger of increased nuclear translocation in AD unknown"]},{"year":2014,"claim":"Identifying MDM2 as an E3 ligase for EID1 and Pcid2 as a stabilizing partner within the CBP/p300-EID1 complex revealed how EID1 turnover gates developmental gene expression in ESCs.","evidence":"Co-IP, K48-linkage ubiquitylation assay, and Pcid2 KO in mouse and human ESCs","pmids":["24167073"],"confidence":"Medium","gaps":["Relative contributions of MDM2 versus other ligases not quantified","Structural basis of Pcid2 blocking MDM2 not defined"]},{"year":2014,"claim":"Demonstrating direct EID1 binding to SHP and E2F1 and co-occupancy of the Egr-1 promoter extended EID1 repression to E2F1-driven transcription on specific chromatin targets.","evidence":"GST pull-down, ChIP, and reporter assays in hepatoma and stellate cells","pmids":["24619556"],"confidence":"Medium","gaps":["Generality of EID1-SHP corepression beyond Egr-1 untested","Recruitment hierarchy among EID1, SHP, and E2F1 unresolved"]},{"year":2015,"claim":"Reconstituting SCF(FBXO21)-mediated polyubiquitylation of a modular EID1 degron overlapping its pRB-binding domain defined the principal pathway controlling EID1 stability in cycling and quiescent cells.","evidence":"In vitro ubiquitylation, in vivo Co-IP and interaction mapping, degron mutagenesis, CRISPR/Cas9 disruption of FBXO21, and proteasome inhibition; two independent labs","pmids":["26631746","26085330"],"confidence":"High","gaps":["Signals controlling FBXO21 substrate recognition not defined","Interplay between FBXO21 and MDM2 pathways not resolved"]},{"year":2015,"claim":"Implicating palmitoylation in EID1 turnover and CBP/p300 activity proposed a lipid modification as an additional regulatory layer at the NSC self-renewal/differentiation switch.","evidence":"2-bromopalmitate inhibitor treatment with NSC differentiation, cell-cycle, and HAT activity assays","pmids":["26497028"],"confidence":"Low","gaps":["Palmitoylation inferred from inhibitor treatment without direct acylation assay or site mutagenesis","Modified residues unidentified","Mechanistic link to degradation not established"]},{"year":2019,"claim":"Knockout of EID1 reducing NSC proliferation and attenuating PI3K/AKT/GSK3β signaling with cognitive deficits revealed a positive, partner-independent requirement for EID1 in neural development.","evidence":"Knockout mice, neurosphere and CCK-8 assays, Western blotting of pathway components, and behavioral testing","pmids":["30926163"],"confidence":"Medium","gaps":["Direct molecular link between EID1 and PI3K/AKT/GSK3β not established","Reconciliation with EID1's transcriptional-repressor role unclear"]},{"year":2020,"claim":"Showing nuclear-speckle localization and direct GPDH promoter binding with repression of lipid accumulation provided direct chromatin-level evidence for EID1 action at an adipogenic target gene.","evidence":"Confocal microscopy, ChIP for GPDH promoter, DNA microarray, and 3T3-L1 overexpression","pmids":["32056205"],"confidence":"Medium","gaps":["Whether EID1 binds DNA directly or via partners not resolved","Functional integration of GPDH repression with PPARγ/pRB axes unclear"]},{"year":null,"claim":"How EID1's opposing context-dependent roles—repressing differentiation genes versus being required for stem-cell proliferation and differentiation—are reconciled at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking EID1 abundance, partner identity, and lineage outcome","No structural data on the CBP/p300-EID1 complex","Direct DNA-binding capacity versus recruitment by partners undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,12]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,10,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,5]}],"complexes":["SCF(FBXO21) ubiquitin ligase complex (substrate)","CBP/p300-EID1 complex"],"partners":["CREBBP","EP300","FBXO21","MDM2","PCID2","NDN","RB1","NR0B2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6B2","full_name":"EP300-interacting inhibitor of differentiation 1","aliases":["21 kDa pRb-associated protein","CREBBP/EP300 inhibitory protein 1","E1A-like inhibitor of differentiation 1","EID-1"],"length_aa":187,"mass_kda":20.9,"function":"Interacts with RB1 and EP300 and acts as a repressor of MYOD1 transactivation. Inhibits EP300 and CBP histone acetyltransferase activity. May be involved in coupling cell cycle exit to the transcriptional activation of genes required for cellular differentiation. May act as a candidate coinhibitory factor for NR0B2 that can be directly linked to transcription inhibitory mechanisms","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y6B2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EID1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EID1","total_profiled":1310},"omim":[{"mim_id":"612986","title":"EP300-INTERACTING INHIBITOR OF DIFFERENTIATION 3; EID3","url":"https://www.omim.org/entry/612986"},{"mim_id":"609773","title":"EP300-INTERACTING INHIBITOR OF DIFFERENTIATION 2; EID2","url":"https://www.omim.org/entry/609773"},{"mim_id":"605894","title":"EP300-INTERACTING INHIBITOR OF DIFFERENTIATION 1; EID1","url":"https://www.omim.org/entry/605894"},{"mim_id":"605179","title":"GAS8 ANTISENSE RNA 1, NONCODING; GAS8AS1","url":"https://www.omim.org/entry/605179"}],"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/EID1"},"hgnc":{"alias_symbol":["EID-1"],"prev_symbol":["C15orf3","CRI1"]},"alphafold":{"accession":"Q9Y6B2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6B2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6B2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6B2-F1-predicted_aligned_error_v6.png","plddt_mean":56.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EID1","jax_strain_url":"https://www.jax.org/strain/search?query=EID1"},"sequence":{"accession":"Q9Y6B2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6B2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6B2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6B2"}},"corpus_meta":[{"pmid":"20486779","id":"PMC_20486779","title":"MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10828624","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.19.24313956","title":"Increased atherogenicity in mood disorders: a systematic review, meta-analysis and meta-regression","date":"2024-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.19.24313956","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12453,"output_tokens":3282,"usd":0.043294,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10729,"output_tokens":4128,"usd":0.078423,"stage2_stop_reason":"end_turn"},"total_usd":0.121717,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"EID1 (C15orf3) encodes a novel human protein of 187 amino acids (predicted 20.8 kDa) located on chromosome 15q21.1→q21.2, with ubiquitous expression in adult tissues and conserved homologs in rat and mouse.\",\n      \"method\": \"cDNA cloning, Northern blot, radiation hybrid mapping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct molecular characterization of the gene/protein, single lab, single study\",\n      \"pmids\": [\"10828624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EID-1 inhibits transcriptional activation of MyoD-responsive promoters required for myogenic differentiation; necdin interacts with EID-1 (identified by cytoplasmic two-hybrid screen), relieves EID-1-dependent repression of myogenic promoters, extends the half-life of EID-1, and relocalizes EID-1 from the nucleus to the cytoplasm when co-expressed.\",\n      \"method\": \"Yeast two-hybrid screen, transactivation assay, co-expression in transfected cells, pulse-chase half-life measurement, subcellular localization imaging\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (two-hybrid, transactivation assay, localization), single lab\",\n      \"pmids\": [\"18557765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EID-1 interacts with the AF-2 domain of the orphan nuclear receptor SF-1, competes with coactivator SRC-1, and represses SF-1 transactivation but not LRH-1, ERRγ, or mCAR transactivation; EID-1 colocalizes with SF-1 in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, transient transfection transactivation assay, colocalization imaging\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays (Y2H + GST pull-down) plus functional transactivation assay, single lab\",\n      \"pmids\": [\"18182853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EID1 nuclear translocation is increased in cortical neurons of Alzheimer's disease patient brains; overexpression of EID1 in transgenic mice leads to increased nuclear localization in neurons, disrupted neurofilament organization, astrogliosis, reduced hippocampal long-term potentiation, and impaired spatial learning and memory, likely through inhibition of CBP/p300-mediated histone and p53 acetylation.\",\n      \"method\": \"Immunofluorescence/immunohistochemistry in human AD brains and transgenic mice, LTP electrophysiology, spatial memory behavioral assays, transgenic mouse generation\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo methods (transgenic mouse, electrophysiology, behavior), single lab\",\n      \"pmids\": [\"22186421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EID1 directly interacts with SHP (NR0B2) and E2F1 proteins (confirmed by GST pull-down); EID1 and SHP associate with the Egr-1 promoter (confirmed by chromatin immunoprecipitation) and together repress E2F1-mediated Egr-1 transactivation in hepatoma and stellate cells.\",\n      \"method\": \"GST pull-down, chromatin immunoprecipitation (ChIP), transient transfection/reporter assay\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction (GST pull-down) plus ChIP and functional reporter assay, single lab\",\n      \"pmids\": [\"24619556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pcid2 associates with EID1 and is present in the CBP/p300-EID1 complex in embryonic stem cells; MDM2 is identified as an E3 ligase mediating K48-linked ubiquitination and proteasomal degradation of EID1; Pcid2 binding to EID1 blocks MDM2 association, thereby stabilizing EID1 and sustaining inhibition of CBP/p300 HAT activity to suppress developmental gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay (K48-linkage), genetic KO of Pcid2 in mouse and human ESCs\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying complex members plus in-cell ubiquitylation assay and genetic KO, single lab\",\n      \"pmids\": [\"24167073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation; the SCF(FBXO21) ubiquitin ligase complex, using FBXO21 as substrate-recognition subunit, polyubiquitylates EID1 both in vitro and in vivo and is required for efficient EID1 degradation in cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma protein-binding domain.\",\n      \"method\": \"In vitro ubiquitylation assay, in vivo co-immunoprecipitation, degron mutagenesis, proteasome inhibitor experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted ubiquitylation assay plus in vivo validation plus mutagenesis of degron, replicated by independent lab (PMID 26085330)\",\n      \"pmids\": [\"26631746\", \"26085330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO21 (central and C-terminal portion) interacts with the C-terminal region of EID1 in transfected cells; FBXO21 overexpression downregulates EID1, FBXO21 gene disruption (CRISPR/Cas9) stabilizes EID1 and causes its accumulation in cytoplasm and nucleus; in vitro ubiquitylation assay confirms EID1 is a direct substrate of SCF(FBXO21).\",\n      \"method\": \"Co-immunoprecipitation in transfected cells, CRISPR/Cas9 gene disruption, in vitro ubiquitylation assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation reconstitution plus genetic KO plus interaction mapping, consistent with independent lab (PMID 26631746)\",\n      \"pmids\": [\"26085330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Palmitoylation modifies EID1; this modification regulates EID1 protein degradation and CBP/p300 histone acetyltransferase activity at the switch between self-renewal and differentiation of neural stem cells.\",\n      \"method\": \"Palmitoylation inhibitor (2-bromopalmitate) treatment, functional assays of NSC differentiation and cell cycle exit, HAT activity assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — palmitoylation modification inferred from inhibitor treatment rather than direct acylation assay or mutagenesis; single lab, indirect evidence\",\n      \"pmids\": [\"26497028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EID1 overexpression in 3T3-L1 preadipocytes reduces PPARγ ligand-dependent transactivation, decreases triglyceride stores, and increases expression of UCP1 and PGC-1α (brown fat markers); EID1 binds to pRB at the onset of adipocyte differentiation and may act to reduce pRB levels.\",\n      \"method\": \"Overexpression in 3T3-L1 cells, transactivation assay, co-immunoprecipitation (EID1-pRB binding), gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for pRB interaction, functional assays without mechanistic pathway reconstitution, single lab\",\n      \"pmids\": [\"20541531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-138 directly targets the 3' UTR of EID1 mRNA (validated by luciferase reporter assay) and negatively regulates EID1 expression; knockdown of EID1 by RNA interference inhibits adipocyte differentiation of human adipose-derived mesenchymal stem cells.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, adipogenic differentiation assay\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter validation plus loss-of-function (siRNA) with defined cellular phenotype, single lab\",\n      \"pmids\": [\"20486779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EID1 knockout in mice reduces neural stem cell (NSC) proliferation and neurosphere formation; loss of EID1 attenuates PI3K/AKT/GSK3β signaling pathway activity in NSCs, and EID1-KO mice show poorer learning and memory and smaller neonatal telencephalon volume.\",\n      \"method\": \"Knockout mouse generation, NSC isolation, neurosphere assay, CCK-8 proliferation assay, Western blotting of PI3K/AKT/GSK3β pathway components, behavioral testing\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts and pathway analysis, single lab\",\n      \"pmids\": [\"30926163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EID1 localizes to the nucleus of preadipocytes in speckles and binds to the promoter sequence of glycerol-3-phosphate dehydrogenase (GPDH); EID1 overexpression during adipocyte differentiation downregulates GPDH expression and inhibits lipid accumulation in 3T3-L1 cells.\",\n      \"method\": \"Confocal microscopy (nuclear localization), ChIP (EID1 binding to GPDH promoter), DNA microarray, overexpression in 3T3-L1 cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for promoter binding plus subcellular localization and functional overexpression phenotype, single lab\",\n      \"pmids\": [\"32056205\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EID1 is a short-lived nuclear protein that inhibits CBP/p300 histone acetyltransferase activity and represses the transcription of differentiation-promoting genes; its abundance is tightly controlled by the SCF(FBXO21) E3 ubiquitin ligase complex, which recognizes a peptidic degron overlapping the retinoblastoma protein-binding domain and mediates polyubiquitylation and proteasomal degradation of EID1, while binding partners such as Pcid2 or necdin can stabilize EID1 by blocking this degradation pathway or relocalizing it from the nucleus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EID1 is a short-lived, ubiquitously expressed nuclear protein that functions as a transcriptional corepressor by inhibiting CBP/p300 histone acetyltransferase activity and thereby restraining differentiation- and developmental-gene programs [#0, #5]. It represses transactivation by multiple sequence-specific factors, including MyoD-responsive myogenic promoters [#1], the orphan nuclear receptor SF-1—where it competes with the coactivator SRC-1 [#2]—and E2F1 at the Egr-1 promoter in concert with SHP/NR0B2 [#4]; EID1 also binds the retinoblastoma protein (pRB) [#9] and occupies target promoters directly, as shown for the GPDH promoter in adipocytes [#12]. Through these activities EID1 acts as a brake on lineage commitment: it suppresses adipogenic and brown-fat gene programs [#9, #12], yet is itself required for adipocyte differentiation of mesenchymal stem cells and for neural stem cell proliferation, where its loss attenuates PI3K/AKT/GSK3\\u03b2 signaling and impairs learning and memory [#10, #11]. EID1 abundance is the dominant control point: it carries a modular peptidic degron overlapping its pRB-binding domain that is recognized by the SCF(FBXO21) ubiquitin ligase for polyubiquitylation and proteasomal degradation [#6, #7], with MDM2 additionally mediating K48-linked ubiquitination [#5]; binding partners counteract this turnover, as necdin stabilizes EID1 and relocalizes it to the cytoplasm [#1] and Pcid2 blocks MDM2 association to sustain CBP/p300 inhibition in embryonic stem cells [#5]. Excess nuclear EID1 is pathologically relevant: it accumulates in cortical neurons of Alzheimer's disease brains, and its overexpression in mice disrupts neurofilament organization, reduces long-term potentiation, and impairs spatial memory, consistent with loss of CBP/p300-mediated histone and p53 acetylation [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the gene's existence and basic features defined EID1 as a conserved, ubiquitously expressed human protein available for functional study.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and radiation hybrid mapping of the 187-aa protein\",\n      \"pmids\": [\"10828624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned at cloning\", \"No subcellular localization or interaction partners defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying EID1 as a corepressor of the nuclear receptor SF-1 that competes with SRC-1 established a coactivator-displacement mechanism for its transcriptional repression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and transactivation/colocalization assays in mammalian cells\",\n      \"pmids\": [\"18182853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for SF-1 over related receptors not mechanistically explained\", \"Did not link repression to CBP/p300 inhibition directly\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing EID-1 inhibits MyoD-responsive myogenic promoters and is regulated by necdin connected EID1 repression to a differentiation program and to partner-controlled stability and localization.\",\n      \"evidence\": \"Yeast two-hybrid, transactivation assays, pulse-chase half-life, and subcellular localization in transfected cells\",\n      \"pmids\": [\"18557765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of necdin-driven nuclear-to-cytoplasmic relocalization unresolved\", \"How relocalization relieves repression not biochemically defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining EID1 as both a repressor of PPAR\\u03b3/brown-fat programs and a pRB-binding, miR-138-regulated, differentiation-required factor placed EID1 at a node controlling adipogenic commitment.\",\n      \"evidence\": \"3T3-L1 overexpression with transactivation and Co-IP assays; luciferase 3'UTR validation and siRNA knockdown in adipose-derived MSCs\",\n      \"pmids\": [\"20541531\", \"20486779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposing roles (represses PPAR\\u03b3 yet required for differentiation) not reconciled\", \"pRB interaction rests on a single Co-IP\", \"Direct promoter occupancy not yet shown at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking nuclear EID1 accumulation to Alzheimer's pathology and to in vivo synaptic and cognitive deficits established a disease-relevant consequence of CBP/p300 inhibition.\",\n      \"evidence\": \"Immunostaining of human AD brains, transgenic mouse overexpression, LTP electrophysiology, and spatial memory testing\",\n      \"pmids\": [\"22186421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of CBP/p300 inhibition inferred rather than directly demonstrated\", \"Trigger of increased nuclear translocation in AD unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying MDM2 as an E3 ligase for EID1 and Pcid2 as a stabilizing partner within the CBP/p300-EID1 complex revealed how EID1 turnover gates developmental gene expression in ESCs.\",\n      \"evidence\": \"Co-IP, K48-linkage ubiquitylation assay, and Pcid2 KO in mouse and human ESCs\",\n      \"pmids\": [\"24167073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of MDM2 versus other ligases not quantified\", \"Structural basis of Pcid2 blocking MDM2 not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating direct EID1 binding to SHP and E2F1 and co-occupancy of the Egr-1 promoter extended EID1 repression to E2F1-driven transcription on specific chromatin targets.\",\n      \"evidence\": \"GST pull-down, ChIP, and reporter assays in hepatoma and stellate cells\",\n      \"pmids\": [\"24619556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of EID1-SHP corepression beyond Egr-1 untested\", \"Recruitment hierarchy among EID1, SHP, and E2F1 unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reconstituting SCF(FBXO21)-mediated polyubiquitylation of a modular EID1 degron overlapping its pRB-binding domain defined the principal pathway controlling EID1 stability in cycling and quiescent cells.\",\n      \"evidence\": \"In vitro ubiquitylation, in vivo Co-IP and interaction mapping, degron mutagenesis, CRISPR/Cas9 disruption of FBXO21, and proteasome inhibition; two independent labs\",\n      \"pmids\": [\"26631746\", \"26085330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling FBXO21 substrate recognition not defined\", \"Interplay between FBXO21 and MDM2 pathways not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicating palmitoylation in EID1 turnover and CBP/p300 activity proposed a lipid modification as an additional regulatory layer at the NSC self-renewal/differentiation switch.\",\n      \"evidence\": \"2-bromopalmitate inhibitor treatment with NSC differentiation, cell-cycle, and HAT activity assays\",\n      \"pmids\": [\"26497028\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Palmitoylation inferred from inhibitor treatment without direct acylation assay or site mutagenesis\", \"Modified residues unidentified\", \"Mechanistic link to degradation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Knockout of EID1 reducing NSC proliferation and attenuating PI3K/AKT/GSK3\\u03b2 signaling with cognitive deficits revealed a positive, partner-independent requirement for EID1 in neural development.\",\n      \"evidence\": \"Knockout mice, neurosphere and CCK-8 assays, Western blotting of pathway components, and behavioral testing\",\n      \"pmids\": [\"30926163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between EID1 and PI3K/AKT/GSK3\\u03b2 not established\", \"Reconciliation with EID1's transcriptional-repressor role unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing nuclear-speckle localization and direct GPDH promoter binding with repression of lipid accumulation provided direct chromatin-level evidence for EID1 action at an adipogenic target gene.\",\n      \"evidence\": \"Confocal microscopy, ChIP for GPDH promoter, DNA microarray, and 3T3-L1 overexpression\",\n      \"pmids\": [\"32056205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EID1 binds DNA directly or via partners not resolved\", \"Functional integration of GPDH repression with PPAR\\u03b3/pRB axes unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EID1's opposing context-dependent roles\\u2014repressing differentiation genes versus being required for stem-cell proliferation and differentiation\\u2014are reconciled at the molecular level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking EID1 abundance, partner identity, and lineage outcome\", \"No structural data on the CBP/p300-EID1 complex\", \"Direct DNA-binding capacity versus recruitment by partners undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"SCF(FBXO21) ubiquitin ligase complex (substrate)\",\n      \"CBP/p300-EID1 complex\"\n    ],\n    \"partners\": [\n      \"CREBBP\",\n      \"EP300\",\n      \"FBXO21\",\n      \"MDM2\",\n      \"PCID2\",\n      \"NDN\",\n      \"RB1\",\n      \"NR0B2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}