{"gene":"EID1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2001,"finding":"EID1 (human/mammalian ortholog context) inhibits CBP/p300 histone acetyltransferase activity; the protein directly inhibits differentiation by targeting activated components for ubiquitin-dependent proteolysis as an F-box protein forming SCF complexes","method":"Genetic epistasis in Arabidopsis (plant ortholog), but foundational mechanism established; mammalian EID1 characterized as CBP/p300 inhibitor","journal":"Genes & development","confidence":"Low","confidence_rationale":"Tier 3 — plant ortholog paper; mammalian EID1 CBP/p300 inhibition established by other papers in corpus","pmids":["11316788"],"is_preprint":false},{"year":2015,"finding":"EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation, and this degron is recognized by SCF(FBXO21), which polyubiquitylates EID1 both in vitro and in vivo. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein (Rb)-binding domain.","method":"In vitro ubiquitylation assay, domain mapping, co-immunoprecipitation, proteasome inhibitor rescue, CRISPR/Cas9 FBXO21 knockout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of ubiquitylation + mutagenesis + genetic validation (CRISPR KO), replicated in two independent papers (PMID 26631746 and 26085330)","pmids":["26631746","26085330"],"is_preprint":false},{"year":2015,"finding":"FBXO21 serves as the substrate-recognition subunit of SCF(FBXO21) E3 ligase and directly interacts with the C-terminal region of EID1; FBXO21 gene disruption by CRISPR/Cas9 stabilizes EID1 and leads to its accumulation in both cytoplasm and nucleus.","method":"Co-immunoprecipitation in transfected cells, in vitro ubiquitylation assay, CRISPR/Cas9 knockout, domain mapping","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 — in vitro ubiquitylation plus genetic KO confirmation, consistent with PMID 26631746","pmids":["26085330"],"is_preprint":false},{"year":2014,"finding":"MDM2 is an E3 ligase for K48-linked EID1 ubiquitination and degradation. Pcid2 binds EID1 and prevents its association with MDM2, thereby stabilizing EID1 within the CBP/p300-EID1 complex to suppress HAT activity and developmental gene expression in embryonic stem cells.","method":"Co-immunoprecipitation, ubiquitylation assays, Pcid2 knockout mouse (early embryonic lethality), ESC differentiation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and in vivo genetic KO, but single lab with limited in vitro reconstitution","pmids":["24167073"],"is_preprint":false},{"year":2011,"finding":"EID1 undergoes increased nuclear translocation in cortical neurons of Alzheimer's disease patient brains compared to controls. Transgenic mice overexpressing EID1 in neurons show increased nuclear EID1, reduced CBP/p300-mediated histone and p53 acetylation, disrupted neurofilament organization, astrogliosis, reduced hippocampal LTP, and impaired spatial learning and memory.","method":"Immunofluorescence/fractionation of human AD brain tissue, transgenic mouse model with neuron-specific EID1 overexpression, LTP electrophysiology, Morris water maze","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment tied to functional consequence, transgenic model with multiple phenotypic readouts","pmids":["22186421"],"is_preprint":false},{"year":2010,"finding":"miR-138 directly targets the 3' UTR of EID1 mRNA to repress its expression, and EID1 knockdown inhibits adipogenic differentiation of human adipose-derived mesenchymal stem cells. EID1 functions as a nuclear receptor coregulator required for adipocyte differentiation.","method":"Luciferase reporter assay (3' UTR targeting), RNA interference knockdown, miRNA overexpression, adipogenic differentiation assays","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter validates direct miRNA-3'UTR interaction plus functional KD phenotype, single lab","pmids":["20486779"],"is_preprint":false},{"year":2014,"finding":"EID1 acts as a co-repressor with SHP on the Egr-1 promoter to repress E2F1-mediated Egr-1 transactivation. Direct protein interactions among E2F1, SHP, and EID1 were demonstrated, and all three proteins occupy the Egr-1 promoter in chromatin immunoprecipitation assays.","method":"GST pull-down assay (direct protein interaction), chromatin immunoprecipitation, transient transfection/transactivation assay in hepatoma and stellate cells, E2F1-/- and SHP-/- mouse models","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1–2 — GST pull-down for direct interaction, ChIP for chromatin occupancy, in vivo genetic models, multiple orthogonal methods in single study","pmids":["24619556"],"is_preprint":false},{"year":2008,"finding":"Necdin interacts with EID-1 (identified via cytoplasmic two-hybrid screen) and relieves EID-1-dependent inhibition of MyoD-responsive promoters. Necdin co-expression increases the steady-state half-life of EID-1 and re-localizes EID-1 from the nucleus to the cytoplasm, thereby promoting myoblast differentiation.","method":"Cytoplasmic two-hybrid screen, transactivation assay, pulse-chase half-life measurement, co-transfection with subcellular localization analysis, necdin-deficient mouse embryo limb bud cultures","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (two-hybrid, reporter assay, protein stability, localization, in vivo embryo culture), single lab","pmids":["18557765"],"is_preprint":false},{"year":2007,"finding":"EID-1 interacts with the AF-2 domain of orphan nuclear receptor SF-1 (via yeast two-hybrid and GST pull-down), co-localizes with SF-1 in mammalian cells, and represses SF-1 transactivation by competing with the coactivator SRC-1.","method":"Yeast two-hybrid, GST pull-down, transient transfection transactivation assay, co-localization in mammalian cells, domain mapping (AF-2)","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by GST pull-down and co-localization with functional transactivation assay, single lab","pmids":["18182853"],"is_preprint":false},{"year":2010,"finding":"EID1 overexpression in 3T3-L1 preadipocytes reduces PPARγ ligand-dependent transactivation, decreases triglyceride stores, binds pRB at onset of adipocyte differentiation (potentially reducing pRB levels), and induces expression of brown fat genes UCP1 and PGC-1α.","method":"Overexpression in 3T3-L1 cells, luciferase-based transactivation assay, co-immunoprecipitation (EID1-pRB binding), qRT-PCR/Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, Co-IP for Rb binding, transactivation assay, but limited mechanistic depth","pmids":["20541531"],"is_preprint":false},{"year":2015,"finding":"Palmitoylation modifies EID1 and this modification regulates EID1 protein degradation and CBP/p300 histone acetyltransferase (HAT) activity during the switch between self-renewal and differentiation in neural stem cells (NSCs). Inhibition of palmitoylation (2-bromopalmitate) impairs NSC differentiation and cell cycle exit.","method":"Palmitoylation inhibitor (2-bromopalmitate) treatment, NSC differentiation assays, HAT activity assay, Western blot for EID1 stability","journal":"Molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological inhibitor approach without direct palmitoylation site mapping; single lab, single method class","pmids":["26497028"],"is_preprint":false},{"year":2020,"finding":"EID1 overexpression in preadipocytes suppresses lipid accumulation by inhibiting GPDH (glycerol-3-phosphate dehydrogenase) expression. EID1 localizes to the nucleus in speckles and binds directly to the GPDH promoter.","method":"DNA microarray, confocal microscopy (nuclear speckle localization), chromatin immunoprecipitation (EID1 binding to GPDH promoter), overexpression in 3T3-L1 cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter occupancy; localization tied to transcriptional repression function; single lab","pmids":["32056205"],"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 pathway signaling in NSCs, and Eid1-KO mice show smaller neonatal telencephalon volume and poorer learning and memory.","method":"Eid1 knockout mice, neurosphere assay, CCK-8 proliferation assay, Western blot (PI3K/AKT/GSK3β pathway), immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype and pathway readout, but mechanistic link between EID1 and PI3K/AKT not directly established (single lab)","pmids":["30926163"],"is_preprint":false}],"current_model":"EID1 (EP300-interacting inhibitor of differentiation 1) is a short-lived nuclear protein that inhibits CBP/p300 histone acetyltransferase activity to suppress differentiation-associated gene expression; it is rapidly degraded via SCF(FBXO21)-mediated polyubiquitylation through a modular degron that overlaps its Rb-binding domain, while MDM2-mediated K48 ubiquitylation provides an alternative degradation pathway that is antagonized by Pcid2; EID1 also acts as a transcriptional co-repressor by interacting with nuclear receptors (SF-1) and co-repressors (SHP) to repress target promoters, and its subcellular localization (nuclear vs. cytoplasmic) is regulated by binding partners such as necdin and by palmitoylation, with nuclear accumulation linked to inhibition of histone acetylation and impaired neuronal and myogenic differentiation."},"narrative":{"teleology":[{"year":2001,"claim":"Initial identification established EID1 as an inhibitor of CBP/p300 histone acetyltransferase activity, linking it to differentiation control, though the founding study characterized the plant ortholog.","evidence":"Genetic epistasis in Arabidopsis with cross-reference to mammalian EID1-CBP/p300 interaction","pmids":["11316788"],"confidence":"Low","gaps":["Mammalian mechanism inferred from plant ortholog; direct biochemical reconstitution of mammalian EID1 HAT inhibition not shown in this study","No degradation pathway identified"]},{"year":2007,"claim":"EID1 was shown to function as a co-repressor of nuclear receptor signaling by binding the AF-2 domain of SF-1 and competing with the coactivator SRC-1, extending its role beyond CBP/p300 HAT inhibition to direct transcriptional repression.","evidence":"Yeast two-hybrid, GST pull-down, transactivation assay, domain mapping in mammalian cells","pmids":["18182853"],"confidence":"Medium","gaps":["Endogenous SF-1 target gene regulation by EID1 not demonstrated","No genome-wide identification of nuclear receptor targets"]},{"year":2008,"claim":"Discovery that necdin binds EID1 and re-localizes it from nucleus to cytoplasm revealed that subcellular distribution is a key regulatory mechanism controlling EID1's repressive activity during myogenesis.","evidence":"Cytoplasmic two-hybrid screen, pulse-chase half-life analysis, subcellular localization in co-transfected cells, necdin-deficient mouse embryo cultures","pmids":["18557765"],"confidence":"Medium","gaps":["Mechanism of necdin-mediated cytoplasmic retention not resolved at structural level","No identification of the nuclear export or retention signal in EID1"]},{"year":2010,"claim":"Two studies established EID1's functional involvement in adipogenesis: EID1 knockdown inhibits adipogenic differentiation of mesenchymal stem cells (being a direct target of miR-138), while EID1 overexpression in preadipocytes reduces PPARγ-dependent transactivation and promotes a brown-fat gene program.","evidence":"Luciferase reporter assay for miR-138 targeting of EID1 3ʹUTR; overexpression in 3T3-L1 cells with co-IP for pRB binding and qRT-PCR","pmids":["20486779","20541531"],"confidence":"Medium","gaps":["Opposing effects of EID1 loss vs. gain on adipogenesis suggest context dependence that is unresolved","Mechanism linking EID1-pRB binding to brown fat gene induction not established"]},{"year":2011,"claim":"Nuclear accumulation of EID1 in cortical neurons was linked to Alzheimer's disease pathology, and transgenic neuronal EID1 overexpression demonstrated that excess nuclear EID1 reduces CBP/p300-mediated acetylation, disrupts neurofilament organization, and impairs hippocampal LTP and spatial memory.","evidence":"Immunofluorescence of human AD brains, neuron-specific transgenic mouse model, LTP electrophysiology, Morris water maze","pmids":["22186421"],"confidence":"Medium","gaps":["Causality between EID1 nuclear translocation and AD onset not established","Upstream signals driving EID1 nuclear accumulation in disease remain unknown"]},{"year":2014,"claim":"Two parallel advances resolved EID1 degradation and co-repressor mechanisms: MDM2 was identified as an alternative E3 ligase for K48-linked EID1 ubiquitylation (antagonized by Pcid2 binding), and EID1 was shown to co-occupy the Egr-1 promoter with SHP to repress E2F1-mediated transcription via direct protein–protein–DNA interactions.","evidence":"Co-IP and ubiquitylation assays with Pcid2-KO mouse ESCs (MDM2 pathway); GST pull-down, ChIP, and transactivation assays with E2F1-/- and SHP-/- mice (Egr-1 co-repression)","pmids":["24167073","24619556"],"confidence":"Medium","gaps":["Relative contributions of SCF(FBXO21) vs. MDM2 pathways to EID1 turnover in different cell types unresolved","Structural basis of Pcid2-mediated MDM2 exclusion unknown"]},{"year":2015,"claim":"The primary degradation pathway for EID1 was biochemically reconstituted: SCF(FBXO21) was identified as the E3 ligase that recognizes a modular C-terminal degron overlapping the Rb-binding domain, providing a mechanistic basis for EID1's short half-life and coupling its stability to Rb interaction.","evidence":"In vitro ubiquitylation reconstitution, CRISPR/Cas9 FBXO21 knockout, domain mapping, proteasome inhibitor rescue in two independent studies","pmids":["26631746","26085330"],"confidence":"High","gaps":["Whether Rb binding protects EID1 from FBXO21-mediated degradation in a competitive manner is not directly tested","Degron-recognition surface on FBXO21 not structurally resolved"]},{"year":2015,"claim":"Palmitoylation was identified as a post-translational modification of EID1 that modulates its stability and consequently CBP/p300 HAT activity during neural stem cell differentiation, adding a lipid-modification layer to EID1 regulation.","evidence":"Pharmacological inhibition of palmitoylation (2-bromopalmitate) in neural stem cell differentiation assays with HAT activity and EID1 stability readouts","pmids":["26497028"],"confidence":"Low","gaps":["Palmitoylation site(s) on EID1 not mapped","No genetic confirmation (e.g., palmitoylation-dead mutant)","Effect attributed solely through pharmacological inhibitor without ruling out indirect targets"]},{"year":2019,"claim":"Genetic loss-of-function established an in vivo requirement for EID1 in neural stem cell proliferation: Eid1-knockout mice show reduced neurosphere formation, attenuated PI3K/AKT/GSK3β signaling, smaller telencephalon, and impaired learning and memory.","evidence":"Eid1 knockout mice, neurosphere assay, Western blot for PI3K/AKT/GSK3β pathway components","pmids":["30926163"],"confidence":"Medium","gaps":["Direct biochemical link between EID1 and PI3K/AKT activation not established","Whether phenotype is CBP/p300-dependent or involves a distinct EID1 function is unknown"]},{"year":2020,"claim":"EID1 was shown to directly occupy the GPDH promoter and repress its expression, providing the first evidence that EID1 acts as a direct promoter-binding transcriptional repressor—not solely through CBP/p300 HAT inhibition—to suppress lipid accumulation.","evidence":"ChIP for EID1 at GPDH promoter, confocal microscopy of nuclear speckle localization, DNA microarray, overexpression in 3T3-L1 cells","pmids":["32056205"],"confidence":"Medium","gaps":["Whether EID1 binds DNA directly or is recruited through a partner transcription factor is not determined","Genome-wide EID1 chromatin occupancy map is lacking"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for EID1 inhibition of CBP/p300 HAT activity, (2) whether EID1 binds chromatin directly or exclusively through transcription factor partners, (3) the interplay between SCF(FBXO21) and MDM2 degradation pathways in different physiological contexts, and (4) the identity and functional significance of the palmitoylation site(s).","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of EID1 alone or in complex with CBP/p300","Genome-wide chromatin occupancy profile absent","Cell-type-specific degradation pathway usage not systematically characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,4,6,8,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,8,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,7,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3]}],"complexes":["SCF(FBXO21)"],"partners":["CREBBP","EP300","FBXO21","MDM2","PCID2","NDN","NR5A1","NR0B2"],"other_free_text":[]},"mechanistic_narrative":"EID1 is a short-lived nuclear co-repressor that inhibits CBP/p300 histone acetyltransferase activity to restrain differentiation-associated gene expression programs across multiple lineages including neuronal, myogenic, and adipogenic fates. EID1 is rapidly turned over by SCF(FBXO21)-mediated polyubiquitylation through a C-terminal degron overlapping its retinoblastoma protein-binding domain, and independently by MDM2-catalyzed K48-linked ubiquitylation that is antagonized by Pcid2-dependent stabilization within CBP/p300 complexes [PMID:26631746, PMID:26085330, PMID:24167073]. Beyond HAT inhibition, EID1 functions as a transcriptional co-repressor on specific promoters—it occupies the Egr-1 promoter with SHP to repress E2F1-mediated transcription, represses SF-1 transactivation by competing with coactivator SRC-1, and directly binds the GPDH promoter to suppress lipid accumulation [PMID:24619556, PMID:18182853, PMID:32056205]. EID1 subcellular distribution is dynamically regulated: necdin binding re-localizes EID1 to the cytoplasm to relieve its nuclear repressive function during myogenesis, while nuclear accumulation of EID1 in neurons suppresses histone acetylation and impairs synaptic plasticity and memory [PMID:18557765, PMID:22186421]."},"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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translocation","date":"2024-12-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.22.627358","citation_count":0,"is_preprint":true},{"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":12824,"output_tokens":3371,"usd":0.044519},"stage2":{"model":"claude-opus-4-6","input_tokens":6754,"output_tokens":3034,"usd":0.16443},"total_usd":0.208949,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"EID1 (human/mammalian ortholog context) inhibits CBP/p300 histone acetyltransferase activity; the protein directly inhibits differentiation by targeting activated components for ubiquitin-dependent proteolysis as an F-box protein forming SCF complexes\",\n      \"method\": \"Genetic epistasis in Arabidopsis (plant ortholog), but foundational mechanism established; mammalian EID1 characterized as CBP/p300 inhibitor\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — plant ortholog paper; mammalian EID1 CBP/p300 inhibition established by other papers in corpus\",\n      \"pmids\": [\"11316788\"],\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, and this degron is recognized by SCF(FBXO21), which polyubiquitylates EID1 both in vitro and in vivo. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein (Rb)-binding domain.\",\n      \"method\": \"In vitro ubiquitylation assay, domain mapping, co-immunoprecipitation, proteasome inhibitor rescue, CRISPR/Cas9 FBXO21 knockout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of ubiquitylation + mutagenesis + genetic validation (CRISPR KO), replicated in two independent papers (PMID 26631746 and 26085330)\",\n      \"pmids\": [\"26631746\", \"26085330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO21 serves as the substrate-recognition subunit of SCF(FBXO21) E3 ligase and directly interacts with the C-terminal region of EID1; FBXO21 gene disruption by CRISPR/Cas9 stabilizes EID1 and leads to its accumulation in both cytoplasm and nucleus.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells, in vitro ubiquitylation assay, CRISPR/Cas9 knockout, domain mapping\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ubiquitylation plus genetic KO confirmation, consistent with PMID 26631746\",\n      \"pmids\": [\"26085330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MDM2 is an E3 ligase for K48-linked EID1 ubiquitination and degradation. Pcid2 binds EID1 and prevents its association with MDM2, thereby stabilizing EID1 within the CBP/p300-EID1 complex to suppress HAT activity and developmental gene expression in embryonic stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, Pcid2 knockout mouse (early embryonic lethality), ESC differentiation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and in vivo genetic KO, but single lab with limited in vitro reconstitution\",\n      \"pmids\": [\"24167073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EID1 undergoes increased nuclear translocation in cortical neurons of Alzheimer's disease patient brains compared to controls. Transgenic mice overexpressing EID1 in neurons show increased nuclear EID1, reduced CBP/p300-mediated histone and p53 acetylation, disrupted neurofilament organization, astrogliosis, reduced hippocampal LTP, and impaired spatial learning and memory.\",\n      \"method\": \"Immunofluorescence/fractionation of human AD brain tissue, transgenic mouse model with neuron-specific EID1 overexpression, LTP electrophysiology, Morris water maze\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional consequence, transgenic model with multiple phenotypic readouts\",\n      \"pmids\": [\"22186421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-138 directly targets the 3' UTR of EID1 mRNA to repress its expression, and EID1 knockdown inhibits adipogenic differentiation of human adipose-derived mesenchymal stem cells. EID1 functions as a nuclear receptor coregulator required for adipocyte differentiation.\",\n      \"method\": \"Luciferase reporter assay (3' UTR targeting), RNA interference knockdown, miRNA overexpression, adipogenic differentiation assays\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter validates direct miRNA-3'UTR interaction plus functional KD phenotype, single lab\",\n      \"pmids\": [\"20486779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EID1 acts as a co-repressor with SHP on the Egr-1 promoter to repress E2F1-mediated Egr-1 transactivation. Direct protein interactions among E2F1, SHP, and EID1 were demonstrated, and all three proteins occupy the Egr-1 promoter in chromatin immunoprecipitation assays.\",\n      \"method\": \"GST pull-down assay (direct protein interaction), chromatin immunoprecipitation, transient transfection/transactivation assay in hepatoma and stellate cells, E2F1-/- and SHP-/- mouse models\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — GST pull-down for direct interaction, ChIP for chromatin occupancy, in vivo genetic models, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24619556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Necdin interacts with EID-1 (identified via cytoplasmic two-hybrid screen) and relieves EID-1-dependent inhibition of MyoD-responsive promoters. Necdin co-expression increases the steady-state half-life of EID-1 and re-localizes EID-1 from the nucleus to the cytoplasm, thereby promoting myoblast differentiation.\",\n      \"method\": \"Cytoplasmic two-hybrid screen, transactivation assay, pulse-chase half-life measurement, co-transfection with subcellular localization analysis, necdin-deficient mouse embryo limb bud cultures\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (two-hybrid, reporter assay, protein stability, localization, in vivo embryo culture), 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 orphan nuclear receptor SF-1 (via yeast two-hybrid and GST pull-down), co-localizes with SF-1 in mammalian cells, and represses SF-1 transactivation by competing with the coactivator SRC-1.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, transient transfection transactivation assay, co-localization in mammalian cells, domain mapping (AF-2)\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by GST pull-down and co-localization with functional transactivation assay, single lab\",\n      \"pmids\": [\"18182853\"],\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, binds pRB at onset of adipocyte differentiation (potentially reducing pRB levels), and induces expression of brown fat genes UCP1 and PGC-1α.\",\n      \"method\": \"Overexpression in 3T3-L1 cells, luciferase-based transactivation assay, co-immunoprecipitation (EID1-pRB binding), qRT-PCR/Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP for Rb binding, transactivation assay, but limited mechanistic depth\",\n      \"pmids\": [\"20541531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Palmitoylation modifies EID1 and this modification regulates EID1 protein degradation and CBP/p300 histone acetyltransferase (HAT) activity during the switch between self-renewal and differentiation in neural stem cells (NSCs). Inhibition of palmitoylation (2-bromopalmitate) impairs NSC differentiation and cell cycle exit.\",\n      \"method\": \"Palmitoylation inhibitor (2-bromopalmitate) treatment, NSC differentiation assays, HAT activity assay, Western blot for EID1 stability\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibitor approach without direct palmitoylation site mapping; single lab, single method class\",\n      \"pmids\": [\"26497028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EID1 overexpression in preadipocytes suppresses lipid accumulation by inhibiting GPDH (glycerol-3-phosphate dehydrogenase) expression. EID1 localizes to the nucleus in speckles and binds directly to the GPDH promoter.\",\n      \"method\": \"DNA microarray, confocal microscopy (nuclear speckle localization), chromatin immunoprecipitation (EID1 binding to GPDH promoter), overexpression in 3T3-L1 cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter occupancy; localization tied to transcriptional repression function; single lab\",\n      \"pmids\": [\"32056205\"],\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 pathway signaling in NSCs, and Eid1-KO mice show smaller neonatal telencephalon volume and poorer learning and memory.\",\n      \"method\": \"Eid1 knockout mice, neurosphere assay, CCK-8 proliferation assay, Western blot (PI3K/AKT/GSK3β pathway), immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype and pathway readout, but mechanistic link between EID1 and PI3K/AKT not directly established (single lab)\",\n      \"pmids\": [\"30926163\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EID1 (EP300-interacting inhibitor of differentiation 1) is a short-lived nuclear protein that inhibits CBP/p300 histone acetyltransferase activity to suppress differentiation-associated gene expression; it is rapidly degraded via SCF(FBXO21)-mediated polyubiquitylation through a modular degron that overlaps its Rb-binding domain, while MDM2-mediated K48 ubiquitylation provides an alternative degradation pathway that is antagonized by Pcid2; EID1 also acts as a transcriptional co-repressor by interacting with nuclear receptors (SF-1) and co-repressors (SHP) to repress target promoters, and its subcellular localization (nuclear vs. cytoplasmic) is regulated by binding partners such as necdin and by palmitoylation, with nuclear accumulation linked to inhibition of histone acetylation and impaired neuronal and myogenic differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EID1 is a short-lived nuclear co-repressor that inhibits CBP/p300 histone acetyltransferase activity to restrain differentiation-associated gene expression programs across multiple lineages including neuronal, myogenic, and adipogenic fates. EID1 is rapidly turned over by SCF(FBXO21)-mediated polyubiquitylation through a C-terminal degron overlapping its retinoblastoma protein-binding domain, and independently by MDM2-catalyzed K48-linked ubiquitylation that is antagonized by Pcid2-dependent stabilization within CBP/p300 complexes [PMID:26631746, PMID:26085330, PMID:24167073]. Beyond HAT inhibition, EID1 functions as a transcriptional co-repressor on specific promoters—it occupies the Egr-1 promoter with SHP to repress E2F1-mediated transcription, represses SF-1 transactivation by competing with coactivator SRC-1, and directly binds the GPDH promoter to suppress lipid accumulation [PMID:24619556, PMID:18182853, PMID:32056205]. EID1 subcellular distribution is dynamically regulated: necdin binding re-localizes EID1 to the cytoplasm to relieve its nuclear repressive function during myogenesis, while nuclear accumulation of EID1 in neurons suppresses histone acetylation and impairs synaptic plasticity and memory [PMID:18557765, PMID:22186421].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Initial identification established EID1 as an inhibitor of CBP/p300 histone acetyltransferase activity, linking it to differentiation control, though the founding study characterized the plant ortholog.\",\n      \"evidence\": \"Genetic epistasis in Arabidopsis with cross-reference to mammalian EID1-CBP/p300 interaction\",\n      \"pmids\": [\"11316788\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mammalian mechanism inferred from plant ortholog; direct biochemical reconstitution of mammalian EID1 HAT inhibition not shown in this study\", \"No degradation pathway identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"EID1 was shown to function as a co-repressor of nuclear receptor signaling by binding the AF-2 domain of SF-1 and competing with the coactivator SRC-1, extending its role beyond CBP/p300 HAT inhibition to direct transcriptional repression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, transactivation assay, domain mapping in mammalian cells\",\n      \"pmids\": [\"18182853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous SF-1 target gene regulation by EID1 not demonstrated\", \"No genome-wide identification of nuclear receptor targets\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that necdin binds EID1 and re-localizes it from nucleus to cytoplasm revealed that subcellular distribution is a key regulatory mechanism controlling EID1's repressive activity during myogenesis.\",\n      \"evidence\": \"Cytoplasmic two-hybrid screen, pulse-chase half-life analysis, subcellular localization in co-transfected cells, necdin-deficient mouse embryo cultures\",\n      \"pmids\": [\"18557765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of necdin-mediated cytoplasmic retention not resolved at structural level\", \"No identification of the nuclear export or retention signal in EID1\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies established EID1's functional involvement in adipogenesis: EID1 knockdown inhibits adipogenic differentiation of mesenchymal stem cells (being a direct target of miR-138), while EID1 overexpression in preadipocytes reduces PPARγ-dependent transactivation and promotes a brown-fat gene program.\",\n      \"evidence\": \"Luciferase reporter assay for miR-138 targeting of EID1 3ʹUTR; overexpression in 3T3-L1 cells with co-IP for pRB binding and qRT-PCR\",\n      \"pmids\": [\"20486779\", \"20541531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing effects of EID1 loss vs. gain on adipogenesis suggest context dependence that is unresolved\", \"Mechanism linking EID1-pRB binding to brown fat gene induction not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Nuclear accumulation of EID1 in cortical neurons was linked to Alzheimer's disease pathology, and transgenic neuronal EID1 overexpression demonstrated that excess nuclear EID1 reduces CBP/p300-mediated acetylation, disrupts neurofilament organization, and impairs hippocampal LTP and spatial memory.\",\n      \"evidence\": \"Immunofluorescence of human AD brains, neuron-specific transgenic mouse model, LTP electrophysiology, Morris water maze\",\n      \"pmids\": [\"22186421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between EID1 nuclear translocation and AD onset not established\", \"Upstream signals driving EID1 nuclear accumulation in disease remain unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two parallel advances resolved EID1 degradation and co-repressor mechanisms: MDM2 was identified as an alternative E3 ligase for K48-linked EID1 ubiquitylation (antagonized by Pcid2 binding), and EID1 was shown to co-occupy the Egr-1 promoter with SHP to repress E2F1-mediated transcription via direct protein–protein–DNA interactions.\",\n      \"evidence\": \"Co-IP and ubiquitylation assays with Pcid2-KO mouse ESCs (MDM2 pathway); GST pull-down, ChIP, and transactivation assays with E2F1-/- and SHP-/- mice (Egr-1 co-repression)\",\n      \"pmids\": [\"24167073\", \"24619556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of SCF(FBXO21) vs. MDM2 pathways to EID1 turnover in different cell types unresolved\", \"Structural basis of Pcid2-mediated MDM2 exclusion unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The primary degradation pathway for EID1 was biochemically reconstituted: SCF(FBXO21) was identified as the E3 ligase that recognizes a modular C-terminal degron overlapping the Rb-binding domain, providing a mechanistic basis for EID1's short half-life and coupling its stability to Rb interaction.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, CRISPR/Cas9 FBXO21 knockout, domain mapping, proteasome inhibitor rescue in two independent studies\",\n      \"pmids\": [\"26631746\", \"26085330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rb binding protects EID1 from FBXO21-mediated degradation in a competitive manner is not directly tested\", \"Degron-recognition surface on FBXO21 not structurally resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Palmitoylation was identified as a post-translational modification of EID1 that modulates its stability and consequently CBP/p300 HAT activity during neural stem cell differentiation, adding a lipid-modification layer to EID1 regulation.\",\n      \"evidence\": \"Pharmacological inhibition of palmitoylation (2-bromopalmitate) in neural stem cell differentiation assays with HAT activity and EID1 stability readouts\",\n      \"pmids\": [\"26497028\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Palmitoylation site(s) on EID1 not mapped\", \"No genetic confirmation (e.g., palmitoylation-dead mutant)\", \"Effect attributed solely through pharmacological inhibitor without ruling out indirect targets\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic loss-of-function established an in vivo requirement for EID1 in neural stem cell proliferation: Eid1-knockout mice show reduced neurosphere formation, attenuated PI3K/AKT/GSK3β signaling, smaller telencephalon, and impaired learning and memory.\",\n      \"evidence\": \"Eid1 knockout mice, neurosphere assay, Western blot for PI3K/AKT/GSK3β pathway components\",\n      \"pmids\": [\"30926163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between EID1 and PI3K/AKT activation not established\", \"Whether phenotype is CBP/p300-dependent or involves a distinct EID1 function is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"EID1 was shown to directly occupy the GPDH promoter and repress its expression, providing the first evidence that EID1 acts as a direct promoter-binding transcriptional repressor—not solely through CBP/p300 HAT inhibition—to suppress lipid accumulation.\",\n      \"evidence\": \"ChIP for EID1 at GPDH promoter, confocal microscopy of nuclear speckle localization, DNA microarray, overexpression in 3T3-L1 cells\",\n      \"pmids\": [\"32056205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EID1 binds DNA directly or is recruited through a partner transcription factor is not determined\", \"Genome-wide EID1 chromatin occupancy map is lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for EID1 inhibition of CBP/p300 HAT activity, (2) whether EID1 binds chromatin directly or exclusively through transcription factor partners, (3) the interplay between SCF(FBXO21) and MDM2 degradation pathways in different physiological contexts, and (4) the identity and functional significance of the palmitoylation site(s).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of EID1 alone or in complex with CBP/p300\", \"Genome-wide chromatin occupancy profile absent\", \"Cell-type-specific degradation pathway usage not systematically characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 4, 6, 8, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 7, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"SCF(FBXO21)\"\n    ],\n    \"partners\": [\n      \"CREBBP\",\n      \"EP300\",\n      \"FBXO21\",\n      \"MDM2\",\n      \"PCID2\",\n      \"NDN\",\n      \"NR5A1\",\n      \"NR0B2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}