Affinage

EID1

EP300-interacting inhibitor of differentiation 1 · UniProt Q9Y6B2

Length
187 aa
Mass
20.9 kDa
Annotated
2026-04-28
24 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 Low

    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

    PMID:11316788

    Open questions at the time
    • Mammalian mechanism inferred from plant ortholog; direct biochemical reconstitution of mammalian EID1 HAT inhibition not shown in this study
    • No degradation pathway identified
  2. 2007 Medium

    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

    PMID:18182853

    Open questions at the time
    • Endogenous SF-1 target gene regulation by EID1 not demonstrated
    • No genome-wide identification of nuclear receptor targets
  3. 2008 Medium

    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

    PMID:18557765

    Open questions at the time
    • Mechanism of necdin-mediated cytoplasmic retention not resolved at structural level
    • No identification of the nuclear export or retention signal in EID1
  4. 2010 Medium

    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

    PMID:20486779 PMID:20541531

    Open questions at the time
    • 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
  5. 2011 Medium

    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

    PMID:22186421

    Open questions at the time
    • Causality between EID1 nuclear translocation and AD onset not established
    • Upstream signals driving EID1 nuclear accumulation in disease remain unknown
  6. 2014 Medium

    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)

    PMID:24167073 PMID:24619556

    Open questions at the time
    • Relative contributions of SCF(FBXO21) vs. MDM2 pathways to EID1 turnover in different cell types unresolved
    • Structural basis of Pcid2-mediated MDM2 exclusion unknown
  7. 2015 High

    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

    PMID:26085330 PMID:26631746

    Open questions at the time
    • 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
  8. 2015 Low

    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

    PMID:26497028

    Open questions at the time
    • 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
  9. 2019 Medium

    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

    PMID:30926163

    Open questions at the time
    • 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
  10. 2020 Medium

    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

    PMID:32056205

    Open questions at the time
    • Whether EID1 binds DNA directly or is recruited through a partner transcription factor is not determined
    • Genome-wide EID1 chromatin occupancy map is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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).
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CREBBPEP300FBXO21MDM2NDNNR0B2NR5A1PCID2
Complex memberships
SCF(FBXO21)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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 Genetic epistasis in Arabidopsis (plant ortholog), but foundational mechanism established; mammalian EID1 characterized as CBP/p300 inhibitor Genes & development Low 11316788
2015 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. In vitro ubiquitylation assay, domain mapping, co-immunoprecipitation, proteasome inhibitor rescue, CRISPR/Cas9 FBXO21 knockout Proceedings of the National Academy of Sciences of the United States of America High 26085330 26631746
2015 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. Co-immunoprecipitation in transfected cells, in vitro ubiquitylation assay, CRISPR/Cas9 knockout, domain mapping Genes to cells : devoted to molecular & cellular mechanisms High 26085330
2014 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. Co-immunoprecipitation, ubiquitylation assays, Pcid2 knockout mouse (early embryonic lethality), ESC differentiation assays Stem cells (Dayton, Ohio) Medium 24167073
2011 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. Immunofluorescence/fractionation of human AD brain tissue, transgenic mouse model with neuron-specific EID1 overexpression, LTP electrophysiology, Morris water maze Neurobiology of disease Medium 22186421
2010 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. Luciferase reporter assay (3' UTR targeting), RNA interference knockdown, miRNA overexpression, adipogenic differentiation assays Stem cells and development Medium 20486779
2014 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. GST pull-down assay (direct protein interaction), chromatin immunoprecipitation, transient transfection/transactivation assay in hepatoma and stellate cells, E2F1-/- and SHP-/- mouse models Hepatology (Baltimore, Md.) High 24619556
2008 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. Cytoplasmic two-hybrid screen, transactivation assay, pulse-chase half-life measurement, co-transfection with subcellular localization analysis, necdin-deficient mouse embryo limb bud cultures Differentiation; research in biological diversity Medium 18557765
2007 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. Yeast two-hybrid, GST pull-down, transient transfection transactivation assay, co-localization in mammalian cells, domain mapping (AF-2) Molecules and cells Medium 18182853
2010 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. Overexpression in 3T3-L1 cells, luciferase-based transactivation assay, co-immunoprecipitation (EID1-pRB binding), qRT-PCR/Western blot Biochemical and biophysical research communications Medium 20541531
2015 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. Palmitoylation inhibitor (2-bromopalmitate) treatment, NSC differentiation assays, HAT activity assay, Western blot for EID1 stability Molecular neurobiology Low 26497028
2020 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. DNA microarray, confocal microscopy (nuclear speckle localization), chromatin immunoprecipitation (EID1 binding to GPDH promoter), overexpression in 3T3-L1 cells Journal of cellular physiology Medium 32056205
2019 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. Eid1 knockout mice, neurosphere assay, CCK-8 proliferation assay, Western blot (PI3K/AKT/GSK3β pathway), immunofluorescence Biochemical and biophysical research communications Medium 30926163

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus EID-1. Stem cells and development 163 20486779
2001 EID1, an F-box protein involved in phytochrome A-specific light signaling. Genes & development 158 11316788
2014 E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology (Baltimore, Md.) 104 24619556
2000 eid1: a new Arabidopsis mutant hypersensitive in phytochrome A-dependent high-irradiance responses. The Plant cell 76 10760243
2006 Functional analysis of EID1, an F-box protein involved in phytochrome A-dependent light signal transduction. The Plant journal : for cell and molecular biology 68 16412087
2018 Mutations in EID1 and LNK2 caused light-conditional clock deceleration during tomato domestication. Proceedings of the National Academy of Sciences of the United States of America 52 29789384
2011 Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease. Neurobiology of disease 38 22186421
2008 The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation. Differentiation; research in biological diversity 27 18557765
2015 Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21. Proceedings of the National Academy of Sciences of the United States of America 24 26631746
2015 Protein Palmitoylation Regulates Neural Stem Cell Differentiation by Modulation of EID1 Activity. Molecular neurobiology 19 26497028
2014 Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of EID1 stability. Stem cells (Dayton, Ohio) 19 24167073
2011 Identification and characterization of Cri1, a locus controlling mortality during Citrobacter rodentium infection in mice. Genes and immunity 15 21326319
2015 FBXO21 mediates the ubiquitylation and proteasomal degradation of EID1. Genes to cells : devoted to molecular & cellular mechanisms 14 26085330
2015 Regulation of human subcutaneous adipocyte differentiation by EID1. Journal of molecular endocrinology 10 26643909
2010 EID1-induces brown-like adipocyte traits in white 3T3-L1 pre-adipocytes. Biochemical and biophysical research communications 9 20541531
2020 Sucralose causes non-selective CD4 and CD8 lymphotoxicity via probable regulation of the MAPK8/APTX/EID1 genes: An in vitro/in silico study. Clinical and experimental pharmacology & physiology 8 32542867
2007 EID-1 interacts with orphan nuclear receptor SF-1 and represses its transactivation. Molecules and cells 8 18182853
2011 The Cri1 locus is the common genetic cause of susceptibility to Citrobacter rodentium infection in C3H and FVB mouse strains. Gut microbes 6 21804358
2022 EID1 plays a protective role in early-onset pre-eclampsia via promoting proliferation and invasion in trophoblast cells. Folia histochemica et cytobiologica 5 35038162
2020 EID1 suppresses lipid accumulation by inhibiting the expression of GPDH in 3T3-L1 preadipocytes. Journal of cellular physiology 3 32056205
2019 Transcriptome profiling in Eid1-KO mice brain shows that Eid1 links cell proliferation in the brain. Gene 3 31381951
2019 EID1 plays a crucial role in proliferation of neural stem cell. Biochemical and biophysical research communications 2 30926163
2023 EID1 promotes the response to canopy shade in Arabidopsis thaliana by repressing the action of phytochrome A. microPublication biology 1 38152059
2000 Identification and expression analysis of C15orf3, a novel gene on chromosome 15q21.1-->q21.2. Cytogenetics and cell genetics 1 10828624