Affinage

EED

Polycomb protein EED · UniProt O75530

Length
441 aa
Mass
50.2 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EED is a WD40-repeat scaffold subunit of the Polycomb Repressive Complex 2 (PRC2) that couples recognition of repressive chromatin marks to propagation of histone H3 lysine-27 trimethylation (PMID:19767730, PMID:15225548). Through an aromatic cage in its C-terminal beta-propeller, EED directly binds histone tails carrying repressive trimethyl-lysine marks (H3K27me3, H3K9me3, H4K20me3), and this binding allosterically activates PRC2 methyltransferase activity, providing the read-and-write feedback loop that spreads H3K27me3 across chromatin; mutation of the aromatic cage (e.g. I363M) preferentially abolishes H3K27me3 in vivo and is lethal at midgestation (PMID:19767730, PMID:27578866). EED scaffolds the catalytic core by binding the N-terminal domain of EZH2 at the bottom face of its WD40 propeller, and the minimal EZH2-EED-SUZ12 trimer is required for methyltransferase activity (PMID:15225548, PMID:17937919, PMID:9742080); disrupting or degrading EED collapses the entire complex and is exploited by allosteric inhibitors (EED226, A-395), interaction-disrupting peptides, and PROTACs that destabilize EZH2 and SUZ12 (PMID:28135235, PMID:28135237, PMID:23974116, PMID:31786184). EED uniquely among PRC2 subunits is also required for global H3K27 monomethylation (PMID:15916951). Beyond canonical PRC2 silencing, EED interacts with histone deacetylases and enhances their activity through a non-canonical, H3K27me3-independent mechanism essential for cardiomyocyte function, with HDAC overexpression rescuing the dilated cardiomyopathy of EED-deficient hearts (PMID:10581039, PMID:28394251). EED targets are directed to chromatin through partners including YY1 and NIPP1, and the complex is regulated developmentally by switching from EZH2 to MLL association (PMID:11158321, PMID:12788942, PMID:17259173). EED is required for diverse developmental programs—maintenance of X-chromosome inactivation, H3K27me3-based genomic imprinting, oligodendrocyte differentiation and remyelination, neurogenesis, microglial synaptic pruning, hematopoiesis, and germ-cell differentiation—acting as a context-dependent epigenetic regulator (PMID:12689588, PMID:30463900, PMID:32851157, PMID:35484239, PMID:31204298, PMID:35679863). A distinct cytoplasmic/membrane pool of EED couples integrin and TNF-R1/HIV-Nef signaling to nSMase2 activation and HIV transcription (PMID:14759364, PMID:20080539).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Establishing that EED is not an orphan PcG protein but a dedicated partner of EZH homologs defined the existence of a discrete EED-EZH2 complex separate from other PcG assemblies.

    Evidence Yeast two-hybrid and reciprocal Co-IP from mouse and human cells, with mutagenesis and specificity controls against HPC2/BMI1/Mph1 complexes

    PMID:9584197 PMID:9584199 PMID:9742080

    Open questions at the time
    • Did not define the enzymatic activity of the complex
    • Functional consequence of EED-RNA binding unresolved
  2. 1998 Medium

    An orthogonal screen revealed a non-nuclear interaction of EED with beta7-integrin cytoplasmic tails, the first hint of a membrane-associated role distinct from chromatin.

    Evidence Yeast two-hybrid screen and co-precipitation from transfected cells with deletion/point mutagenesis mapping

    PMID:9765275

    Open questions at the time
    • Physiological trigger and signaling output of the integrin interaction not established
    • Relationship to nuclear EED pool unclear
  3. 1999 High

    Linking EED to histone deacetylases showed that EED-mediated repression involves deacetylation, foreshadowing a non-PRC2 chromatin-modifying activity.

    Evidence In vitro binding, reciprocal Co-IP of HDAC activity, transcriptional reporter assay with TSA rescue and PcG specificity controls

    PMID:10581039

    Open questions at the time
    • Which HDAC isoforms and the in vivo significance not defined at the time
    • Mechanism of HDAC activation unaddressed
  4. 2001 Medium

    Identification of YY1 as an EED partner provided a sequence-specific DNA-targeting mechanism to recruit the EED-EZH2 complex to genes.

    Evidence Co-IP, yeast two-hybrid, and Xenopus axis-induction functional assay

    PMID:11158321

    Open questions at the time
    • Direct demonstration of YY1-dependent recruitment at endogenous loci lacking
    • Single lab
  5. 2003 Medium

    Demonstration that the Eed-Enx1 complex establishes and stably maintains repressive histone methylation on the inactive X across mitosis defined a mechanism for heritable epigenetic silencing.

    Evidence Immunofluorescence on mitotic chromosomes in TS cells and genetic loss-of-function in mouse embryos with modification-specific antibodies; NIPP1-PP1-HDAC2 ternary complex mapping

    PMID:12123576 PMID:12689588 PMID:12788942

    Open questions at the time
    • Distinction between H3K9 vs H3K27 methylation contribution to Xi unresolved
    • Mechanism of mitotic retention not molecularly defined
  6. 2004 High

    Reconstitution defined the minimal enzymatic unit of PRC2, showing EED is an obligate component of an active H3K27 methyltransferase rather than an accessory factor.

    Evidence In vitro HMTase reconstitution with defined subunit combinations, RNAi knockdown and ChIP for Hox derepression

    PMID:15225548

    Open questions at the time
    • How H3K27me3 read-out feeds back on activity not yet shown
    • Role of AEBP2 mechanistically undefined
  7. 2004 Medium

    A signaling-coupled cytoplasmic function emerged, showing EED relocalizes to the plasma membrane upon integrin or HIV-Nef stimulation to control viral transcription.

    Evidence Co-IP, subcellular fractionation, immunofluorescence, transcription reporter assay, RNAi; plus HIV MA and integrase binding/integration assays

    PMID:14610174 PMID:14759364 PMID:9880543

    Open questions at the time
    • How nuclear PRC2 EED is repurposed for membrane signaling unclear
    • Endogenous relevance outside HIV infection unestablished
  8. 2005 Medium

    Genetic dissection separated EED from other PRC2 subunits by showing it is uniquely required for global H3K27 monomethylation, implying an additional or distinct enzymatic context.

    Evidence Eed knockout mouse with methylation-state-specific antibody readouts

    PMID:15916951

    Open questions at the time
    • The enzyme responsible for EED-dependent H3K27me1 not identified
    • Mechanistic basis for the monomethylation-specific requirement unknown
  9. 2007 High

    Structural definition of the EZH2-EED interface and the histone-binding/allosteric activation mechanism converted EED into a structurally tractable scaffold and an allosteric switch for PRC2.

    Evidence X-ray crystallography of EED-EZH2 peptide and EED-trimethyl-lysine peptide complexes with structure-based mutagenesis and Drosophila genetics; isoform analysis showed isoforms do not control methylation level

    PMID:17937919 PMID:17997413 PMID:19767730

    Open questions at the time
    • Structure of the full PRC2 holocomplex not resolved here
    • How H3K9me3/H4K20me3 binding contributes in vivo unclear
  10. 2007 Medium

    Discovery that EED switches from EZH2 to MLL during brain maturation revealed that complex composition, not just EED itself, dictates substrate specificity and physiological output.

    Evidence Co-IP of Eed-Mll complex, genetic double-heterozygote epistasis, histone modification westerns, synaptic plasticity electrophysiology

    PMID:17259173

    Open questions at the time
    • Trigger for the EZH2-to-MLL switch unknown
    • Whether the switch occurs in other tissues unaddressed
  11. 2008 Medium

    Placing Eed downstream of STAT3 and Oct-3/4 defined how stem-cell transcription factors maintain PRC2-dependent silencing of differentiation genes.

    Evidence Reporter assay, ChIP, EMSA, dominant-negative and RNAi in mouse ES cells

    PMID:18201968

    Open questions at the time
    • Direct vs indirect contribution of EED loss to gene upregulation not fully separated
    • Single lab
  12. 2016 High

    Knock-in mutagenesis of the aromatic cage proved the read-and-write model in vivo, showing H3K27me3 recognition by EED is essential for mark propagation, embryonic viability, and hematopoietic stem-cell control.

    Evidence EED I363M knock-in mouse, histone modification westerns, hematopoietic stem/progenitor assays, Lgals3 derepression analysis

    PMID:27578866

    Open questions at the time
    • Tissue-specific thresholds for aromatic-cage dependence not mapped
    • Contribution of residual non-cage functions unresolved
  13. 2017 High

    Small-molecule and peptide tools targeting the EED aromatic cage and the EZH2-EED interface established EED as a druggable allosteric and scaffolding node, including against EZH2-inhibitor-resistant tumors.

    Evidence X-ray co-crystallography, in vitro PRC2 assays, cellular H3K27me3 readouts, xenograft/leukemia models for EED226, A-395, and SAH-EZH2 peptides

    PMID:23974116 PMID:28135235 PMID:28135237

    Open questions at the time
    • Whether allosteric inhibition affects non-canonical EED functions untested
    • Resistance mechanisms to EED-pocket binders not explored
  14. 2017 High

    A genetic and biochemical dissection in the heart revealed a fully non-canonical, H3K27me3-independent EED function: enhancing HDAC activity to maintain gene repression and cardiac function.

    Evidence Cardiac conditional knockout with dilated cardiomyopathy and increased H3K27ac, EED-HDAC Co-IP, HDAC activity assay, and HDAC-overexpression rescue

    PMID:28394251

    Open questions at the time
    • Molecular basis by which EED stimulates HDAC catalysis not defined
    • Whether this HDAC mechanism operates outside cardiomyocytes unknown
  15. 2018 High

    Maternal-knockout experiments established EED as essential for depositing maternal H3K27me3 imprints that drive a non-canonical mode of genomic imprinting.

    Evidence Maternal Eed knockout mouse with RNA-seq and H3K27me3 ChIP-seq showing loss of imprinted expression including Xist

    PMID:30463900

    Open questions at the time
    • How H3K27me3 imprints are targeted to specific loci not addressed
    • Stability of imprints in absence of zygotic EED unresolved
  16. 2023 Medium

    Tissue-specific knockouts and partner studies extended EED's roles to remyelination, neurogenesis, microglial synaptic pruning, germ-cell differentiation, and non-canonical activating chromatin functions, defining it as a context-dependent regulator with both repressive and activating outputs.

    Evidence Conditional knockouts with ChIP-seq/RNA-seq and pathway-specific rescues across OPCs, NSPCs, microglia and PGCs; EED-DNMT1 and EED-BRD4 Co-IPs; ChIP at TE regulators, EMT loci, Tbx3 enhancer, AR and Ccnd1

    PMID:23671187 PMID:25264103 PMID:30609396 PMID:30628724 PMID:31204298 PMID:32851157 PMID:35484239 PMID:35679863 PMID:36923952

    Open questions at the time
    • Mechanism distinguishing repressive vs BRD4-coupled activating EED functions unclear
    • AR-EED interaction rests on a single low-confidence Co-IP
    • How cell-type-specific partner choice is determined unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single EED scaffold is partitioned between canonical PRC2 methyltransferase activation, non-canonical HDAC stimulation, BRD4/H3K27ac-coupled activation, and membrane signaling, and what governs this partitioning, remains unresolved.
  • No structural or biochemical model unifying canonical and non-canonical EED activities
  • Signals that route EED between nuclear and membrane pools unknown
  • Determinants of partner-complex switching not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2
Partners
BRD4DNMT1EZH2HDACNIPP1NSMASE2SUZ12YY1
Complex memberships
EED-MLL complexPRC2

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 The C-terminal domain of EED specifically binds histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks (H3K27me3, H3K9me3, H4K20me3), and this binding allosterically activates the methyltransferase activity of PRC2. Mutations in EED that prevent recognition of repressive trimethyl-lysine marks abolish PRC2 activation in vitro and reduce global H3K27 methylation in Drosophila, establishing a model for propagation of the H3K27me3 mark. Biochemical binding assays, in vitro methyltransferase assays, structure determination, site-directed mutagenesis, Drosophila genetics Nature High 19767730
2004 The histone methyltransferase activity of the EED-EZH2 complex requires a minimum of three components—EZH2, EED, and SUZ12—while AEBP2 is required for optimal enzymatic activity. SUZ12 knockdown causes genome-wide alteration of H3K27 methylation and upregulation of Hox genes. In vitro HMTase reconstitution assay with individual subunit combinations, stable RNAi knockdown cell line, ChIP assay Molecular Cell High 15225548
1999 EED interacts with histone deacetylase (HDAC) proteins both in vitro and in vivo, and histone deacetylase activity co-immunoprecipitates with EED. The HDAC inhibitor trichostatin A relieves EED-mediated transcriptional repression, demonstrating that PcG-mediated repression by EED involves histone deacetylation. This interaction is specific to EED and not shared by other vertebrate PcG proteins. In vitro binding assay, co-immunoprecipitation, transcriptional reporter assay, HDAC inhibitor treatment Nature Genetics High 10581039
2007 Crystal structure of EED in complex with a 30-residue peptide from EZH2 reveals that the EZH2 peptide binds to the bottom face of the WD-repeat beta-propeller domain of EED. Structure-based mutagenesis identified critical residues from both EED and EZH2 required for their interaction. The structural determinants are conserved in EZH1 and Drosophila E(Z). X-ray crystallography, structure-based mutagenesis, binding assays Structure High 17937919
1998 EED (WAIT-1) specifically interacts with the cytoplasmic tails of beta7-integrins (alpha4beta7 and alphaEbeta7) but not with beta1, beta2, or alphaL integrin subunits. The binding site was mapped to a membrane-proximal region of the beta7 tail with Tyr-735 being critical. Association confirmed by co-precipitation from transfected cells. Yeast two-hybrid screen, co-precipitation from transfected 293 cells, deletion/point mutagenesis mapping Journal of Biological Chemistry Medium 9765275
1998 EED interacts with EZH2 (Enx1/Enx2) in vivo and in vitro via yeast two-hybrid and co-immunoprecipitation. Point mutations T1031A (null allele) and T1040C (hypomorphic allele) in the WD40 domain of EED block Ezh2 binding in yeast, in mammalian cells, and in vitro. EED and Ezh2 also bind RNA in vitro, and RNA alters their interaction. EED acts as a transcriptional repressor when fused to Gal4, and the N-terminal fragment of Ezh2 abolishes this repressor activity. Yeast two-hybrid screen, co-immunoprecipitation from murine cells, in vitro binding with point mutants, Gal4 reporter transcription assay, RNA-binding assay Molecular and Cellular Biology High 9742080
1998 Mouse Eed interacts specifically with Enx1 and Enx2 (mammalian EZH homologs) in vivo, forming a distinct PcG complex. No direct biochemical interaction was found between the Eed/Enx complex and the Mph1-containing PcG complex, indicating functionally distinct PcG complexes exist. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization Molecular and Cellular Biology Medium 9584197
1998 EED (HEED) and EZH2 (Enx1) co-immunoprecipitate from human cells but do not co-immunoprecipitate with HPC2 or BMI1, and do not colocalize with these proteins in nuclear domains, establishing EED-EZH2 as a distinct PcG complex separate from the HPC/HPH complex. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence Molecular and Cellular Biology Medium 9584199
2001 EED specifically interacts with YY1 (the human homolog of Drosophila Pleiohomeotic) but not with proteins of the HPC-HPH PcG complex. This interaction provides a direct link between the EED-EZH2 complex and DNA of target genes. In Xenopus embryos, both Xeed and XYY1 induce ectopic neural axis formation, consistent with functional interaction. Co-immunoprecipitation, yeast two-hybrid, Xenopus microinjection and axis induction assay Molecular and Cellular Biology Medium 11158321
2005 Unlike Suz12 and Ezh2, which are required only for H3K27me2 and H3K27me3, Eed is required for all three levels of H3K27 methylation including global H3K27me1, implicating Eed in PRC2-independent histone methylation activity for monomethylation. Eed knockout mouse genetics, immunofluorescence/western blot with methylation-state-specific antibodies Current Biology Medium 15916951
2007 EED is present as four distinct isoforms produced from in-frame translation start sites. Individual EED isoforms are not required for H3K27me1, H3K27me2, or H3K27me3; instead, the core WD-40 motifs and histone-binding region of EED alone are sufficient for generation of all three methylation marks, demonstrating EED isoforms do not control the number of methyl groups added. Eed isoform characterization, isoform-specific mutant mouse embryo analysis, histone methylation assays Journal of Molecular Biology Medium 17997413
2003 Eed-Enx1 complex is required to establish methylation of histone H3 at lysine 9 and/or lysine 27 on the inactive X chromosome; this methylation is in turn required to stabilize Xi chromatin structure. Localization of Eed-Enx1 to Xi occurs at the onset of Xist expression and is transient, correlating with high complex levels in totipotent cells. Immunofluorescence, genetic loss-of-function analysis (Eed mutant mouse embryos), histone modification antibody staining Developmental Cell Medium 12689588
2002 Eed-Enx1 complexes associate mitotically stably with the inactive X chromosome in trophoblast stem cells (TS cells), as demonstrated by live-cell and fixed imaging, providing a mechanism for maintenance of imprinted X inactivation through cell division. Immunofluorescence on metaphase chromosomes in TS cells, mitotic stability assay Current Biology Medium 12123576
2004 HIV-1 Nef recruits EED from the nucleus to the plasma membrane, and this translocation of EED potently stimulates Tat-dependent HIV transcription. Activation of integrin receptors similarly recruits EED to the plasma membrane and enhances Tat/Nef-mediated transcription, linking membrane-associated activation with transcriptional derepression. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, transcription reporter assay, RNAi knockdown Molecular Cell Medium 14759364
2009 EED physically interacts with the catalytic domain of nSMase2 (neutral sphingomyelinase 2) via its N-terminus, and also binds RACK1. TNF stimulation causes EED to translocate from the nucleus and colocalize with nSMase2 and RACK1 at the TNF-R1 complex. EED knockdown by RNAi completely abrogates TNF-dependent nSMase2 activation, identifying EED as the link coupling TNF-R1 to nSMase2. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, subcellular fractionation, RNAi knockdown with functional nSMase2 activity assay PNAS Medium 20080539
1999 Human EED (HEED) binds to the matrix (MA) protein of HIV-1, with the interaction involving the N-terminal region of MA including the first polybasic signal. Two discrete MA-binding motifs were mapped to residues 388-403 of HEED overlapping the fifth WD repeat. MA and HEED co-localize in the nucleus of co-transfected cells. Yeast two-hybrid, in vitro pull-down, site-directed mutagenesis, phage biopanning, co-localization by immunofluorescence Journal of Biological Chemistry Medium 9880543
2003 EED interacts with HIV-1 integrase (IN) both in vitro and in vivo. The EED-binding site on IN maps to the C-terminal domain (residues 212-264), and two IN-binding sites on EED map to its N-terminal moiety. EED positively stimulates IN-mediated DNA integration in vitro in a dose-dependent manner. EED and IN co-localize in the nucleus and near nuclear pores in HIV-1-infected cells. Yeast two-hybrid, in vitro pull-down, mutagenesis, phage biopanning, in vitro integration assay, immunoelectron microscopy Journal of Virology Medium 14610174
2003 NIPP1 (nuclear inhibitor of PP1) interacts with EED; two EED interaction domains map to the central and C-terminal thirds of NIPP1. (d)G-rich nucleic acids potentiate NIPP1-EED interaction. EED and NIPP1 form a ternary complex with PP1. NIPP1 acts as a transcriptional repressor via its EED interaction domain, and HDAC2 is present in a complex with NIPP1, suggesting NIPP1 functions as a DNA-targeting protein for EED-associated chromatin-modifying enzymes. Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assay, domain mapping Journal of Biological Chemistry Medium 12788942
2017 EED226, a small molecule that directly binds to the H3K27me3-binding pocket (aromatic cage) of EED, induces a conformational change upon binding, leading to allosteric loss of PRC2 methyltransferase activity. X-ray co-crystal structures confirmed the binding mode. EED226 inhibits H3K27 methylation in cells and in vivo, and retains activity against PRC2 with SAM-competitive EZH2-resistant mutations. X-ray co-crystallography, in vitro PRC2 methyltransferase assay, cellular H3K27me3 measurement, xenograft tumor model Nature Chemical Biology High 28135235
2017 A-395 binds to EED in the H3K27me3-binding pocket (demonstrated by structural studies) and prevents allosteric activation of PRC2 catalytic activity. A-395 retains potent activity against cell lines resistant to catalytic EZH2 inhibitors. Structural studies (X-ray crystallography), in vitro PRC2 enzymatic assay, cellular H3K27me3 reduction, resistant cell line testing Nature Chemical Biology High 28135237
2013 SAH-EZH2 stabilized alpha-helix peptides disrupt the EZH2-EED protein-protein interaction, leading to dose-responsive inhibition of H3K27 trimethylation and reduction of EZH2 protein levels. This mechanism is distinct from catalytic domain inhibitors and causes growth arrest and monocyte-macrophage differentiation in MLL-AF9 leukemia cells. Stabilized peptide design, co-immunoprecipitation disruption assay, western blot for H3K27me3 and EZH2 levels, cell differentiation assay Nature Chemical Biology High 23974116
2007 During brain maturation, Eed switches from the PRC2 complex (Eed-EzH2) to associate with the trxG protein Mll, forming a novel Eed-Mll complex with different substrate specificity. The Eed-EzH2 complex in neonatal brain mediates H3K27 trimethylation, while the Eed-Mll complex in adult hippocampus regulates histone H4 acetylation. This developmental switch in complex composition is required for synaptic plasticity. Co-immunoprecipitation, genetic double heterozygote analysis, histone modification western blots, electrophysiological synaptic plasticity assay Journal of Biological Chemistry Medium 17259173
2008 STAT3 and Oct-3/4 directly bind to the promoter region of Eed and transcriptionally activate its expression in mouse ES cells. Loss of STAT3 or Oct-3/4 reduces Eed expression, and subsequent loss of Eed results in loss of H3K27me3 at promoters of differentiation-associated genes, leading to their upregulation. Reporter assay, ChIP, EMSA, dominant-negative STAT3 expression, RNAi knockdown, qRT-PCR Journal of Biological Chemistry Medium 18201968
2017 In postnatal cardiomyocytes, EED interacts with histone deacetylases (HDACs) and enhances their catalytic activity through a non-canonical, H3K27me3-independent mechanism. EED conditional knockout causes dilated cardiomyopathy with upregulation of genes accompanied by increased H3K27ac (not decreased H3K27me3). HDAC overexpression rescues EedCKO heart function and gene expression. EED cardiac conditional knockout mouse, co-immunoprecipitation of EED-HDAC complex, HDAC activity assay, genome-wide chromatin profiling, HDAC overexpression rescue eLife High 28394251
2016 EED aromatic cage integrity (residues Phe97, Trp364, Tyr365) is required for H3K27me3 propagation in vivo. Knock-in mice with the EED I363M mutation (which disrupts the aromatic cage) show preferential reduction of H3K27me3 and die at midgestation. Heterozygous I363M mice show enhanced hematopoietic stem/progenitor cell stemness through derepression of Lgals3, a PRC2 target gene. Knock-in mouse genetics, histone modification western blots, hematopoietic stem cell assays, gene expression analysis PNAS High 27578866
2019 EED-targeted PROTACs bind EED with high affinity (pKD ~9.0), promote ternary complex formation with an E3 ubiquitin ligase, and induce rapid proteasomal degradation not only of EED but also of EZH2 and SUZ12 within the intact PRC2 complex, indicating that EED degradation destabilizes the entire complex. Biochemical HTRF binding assay, western blot for protein degradation, PRC2 enzyme activity assay, cancer cell proliferation assay Cell Chemical Biology Medium 31786184
2018 Maternal EED (as a core PRC2 component) is required for establishing H3K27me3-based genomic imprinting. All H3K27me3-imprinted genes including Xist lose imprinted expression in Eed maternal knockout embryos, demonstrating EED is essential for the deposition of maternal H3K27me3 imprints. Maternal knockout mouse model, RNA-seq for imprinted gene expression, H3K27me3 ChIP-seq Genes & Development High 30463900
2013 EED and KDM6B (H3K27 demethylase) act antagonistically to control PRC2 complex recruitment and H3K27me3 deposition at chromatin domains of TE-specific master regulators CDX2 and GATA3 during blastocyst formation. Ectopic EED gain combined with KDM6B depletion in mouse embryos abolishes CDX2/GATA3 expression in the trophectoderm, causing implantation failure. Conditional overexpression/knockdown in preimplantation mouse embryos, ChIP, immunofluorescence, embryo transfer implantation assay Molecular and Cellular Biology Medium 23671187
2014 EED knockdown antagonizes TGF-β-induced EMT and TGF-β-dependent transcriptional repression of CDH1 and miR-200 family genes. ChIP assays showed EED is recruited to regulatory regions of CDH1 and miR-200 family genes during TGF-β-induced EMT and regulates H3K27 methylation and EZH2 occupancy at these loci. RNAi knockdown, qRT-PCR, morphological EMT analysis, ChIP assay for H3K27me3 and EZH2 occupancy Biochemical and Biophysical Research Communications Medium 25264103
2019 EED directly interacts with androgen receptor (AR) in prostate cancer cells, and EED regulates AR expression levels and AR downstream targets. Disruption of EZH2-EED interaction by astemizole represses EZH2 and AR expression. Co-immunoprecipitation, western blot, small-molecule EZH2-EED disruption International Journal of Cancer Low 30628724
2019 EED binds an intragenic Tbx3 enhancer in ESCs to oppose BAF-complex (Dpf2)-dependent Tbx3 expression and mesendodermal differentiation, establishing antagonistic roles for EED/PRC2 and BAF subunit Dpf2 at the same locus. ChIP-seq, ESC conditional knockout genetics, rescue by Tbx3 overexpression Cell Stem Cell Medium 30609396
2020 EED is required for oligodendrocyte progenitor (OPC) differentiation and CNS remyelination but is dispensable for myelin maintenance. EED conditional knockout causes OPC-to-astrocyte fate switch in a region-specific manner. Mechanistically, EED establishes a chromatin landscape repressing WNT and BMP signaling and senescence-associated programs, and blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Conditional knockout mouse, H3K27me3 ChIP-seq, RNA-seq, WNT/BMP pathway inhibitor rescue experiments Science Advances High 32851157
2022 EED is required in microglia for synaptic pruning during postnatal brain development. Microglial EED deletion results in reduced spine density and impaired synapse density in the hippocampus, accompanied by upregulated expression of phagocytosis-related genes. EED-deficient mice show impaired hippocampus-dependent learning and memory. Microglial conditional knockout, spine/synapse density quantification, RNA-seq of microglia, behavioral learning/memory assays Molecular Psychiatry Medium 35484239
2019 Loss of EED in neural stem/progenitor cells leads to impaired neuronal differentiation and dentate gyrus malformation. EED regulates SOX11 expression through H3K27me1, and overexpression of Sox11 restores neuronal differentiation capacity. EED also regulates Cdkn2a through H3K27me3-dependent silencing to control NSPC proliferation. Neural-specific conditional knockout, immunofluorescence, ChIP for H3K27me1/H3K27me3, Sox11/Cdkn2a overexpression/knockdown rescue experiments Stem Cell Reports Medium 31204298
2023 EED co-immunoprecipitates with the H3K27ac reader BRD4 in smooth muscle cells, and both EED and BRD4 co-occupy the Ccnd1 (cyclinD1) promoter and a repressed locus (P57) simultaneously. EED overexpression increases Ccnd1 mRNA, and this activation is abolished by inhibitors of either the EED/H3K27me3 or BRD4/H3K27ac reader functions. In vivo, EED is upregulated in neointimal lesions, and EED inhibition reduces cyclinD1 and neointima formation. Co-immunoprecipitation, ChIP-qPCR, pharmacological inhibitor experiments, rat carotid artery angioplasty model Molecular Therapy Nucleic Acids Medium 36923952
2022 EED is required for primordial germ cell (PGC) sex-specific differentiation timing in both ovaries and testes, and for X chromosome dosage decompensation in testes. EED and DNMT1 interact in the epiblast to establish a poised repressive H3K27me3/DNA methylation signature that regulates PGC differentiation. EED conditional knockout mouse, H3K27me3 ChIP-seq, whole-genome bisulfite sequencing, co-immunoprecipitation of EED-DNMT1 Developmental Cell Medium 35679863

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 945 19767730
2004 SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Molecular cell 652 15225548
2003 Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Developmental cell 524 12689588
2014 PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature genetics 483 25240281
1999 Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature genetics 436 10581039
2005 The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Current biology : CB 290 15916951
2013 Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nature chemical biology 282 23974116
2017 An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nature chemical biology 258 28135235
1995 The eed mutation disrupts anterior mesoderm production in mice. Development (Cambridge, England) 248 7768172
1998 Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Molecular and cellular biology 206 9584199
2003 Genome imprinting regulated by the mouse Polycomb group protein Eed. Nature genetics 200 12627233
1999 Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes & development 194 10541555
2002 Mitotically stable association of polycomb group proteins eed and enx1 with the inactive x chromosome in trophoblast stem cells. Current biology : CB 181 12123576
2017 The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nature chemical biology 174 28135237
1998 The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo. Development (Cambridge, England) 170 9778508
2019 EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex. Cell chemical biology 167 31786184
2001 The polycomb group protein EED interacts with YY1, and both proteins induce neural tissue in Xenopus embryos. Molecular and cellular biology 153 11158321
2019 Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader. Cell chemical biology 144 31831267
2007 Structural basis of EZH2 recognition by EED. Structure (London, England : 1993) 120 17937919
2006 The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation. Nature cell biology 119 16415857
1998 Interaction of mouse polycomb-group (Pc-G) proteins Enx1 and Enx2 with Eed: indication for separate Pc-G complexes. Molecular and cellular biology 112 9584197
2018 Maternal Eed knockout causes loss of H3K27me3 imprinting and random X inactivation in the extraembryonic cells. Genes & development 106 30463900
2006 The Polycomb group protein EED is dispensable for the initiation of random X-chromosome inactivation. PLoS genetics 93 16680199
2014 Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2. Journal of medicinal chemistry 86 25369470
1998 Point mutations in the WD40 domain of Eed block its interaction with Ezh2. Molecular and cellular biology 86 9742080
2015 A novel mutation in EED associated with overgrowth. Journal of human genetics 76 25787343
2008 Comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, TFPI2/Tfpi2, which requires EHMT2 and EED for allelic-silencing. Genome research 72 18480470
2002 The mouse PcG gene eed is required for Hox gene repression and extraembryonic development. Mammalian genome : official journal of the International Mammalian Genome Society 72 12370779
2004 HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane. Molecular cell 69 14759364
2014 Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer. Journal of cancer research and clinical oncology 63 25326896
2009 The Polycomb group protein EED couples TNF receptor 1 to neutral sphingomyelinase. Proceedings of the National Academy of Sciences of the United States of America 60 20080539
2003 The human polycomb group EED protein interacts with the integrase of human immunodeficiency virus type 1. Journal of virology 60 14610174
2019 Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. International journal of cancer 58 30628724
2007 Developmental regulation of Eed complex composition governs a switch in global histone modification in brain. The Journal of biological chemistry 55 17259173
2016 EED-associated overgrowth in a second male patient. Journal of human genetics 52 27193220
2012 PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ. PloS one 51 23251464
2016 Novel EED mutation in patient with Weaver syndrome. American journal of medical genetics. Part A 50 27868325
2017 Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase. Journal of medicinal chemistry 47 27992714
2013 EED and KDM6B coordinate the first mammalian cell lineage commitment to ensure embryo implantation. Molecular and cellular biology 47 23671187
2008 STAT3 and Oct-3/4 control histone modification through induction of Eed in embryonic stem cells. The Journal of biological chemistry 47 18201968
1998 The human WD repeat protein WAIT-1 specifically interacts with the cytoplasmic tails of beta7-integrins. The Journal of biological chemistry 47 9765275
2017 EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent. eLife 46 28394251
2001 Cell and tissue requirements for the gene eed during mouse gastrulation and organogenesis. Genesis (New York, N.Y. : 2000) 46 11783004
2019 An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response. Cancer research 43 31395608
2000 Rice in deep water: "how to take heed against a sea of troubles". Die Naturwissenschaften 43 11013876
2017 Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2. ACS combinatorial science 42 28165227
2015 Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer. Oncotarget 42 25944687
2007 Molecular and functional mapping of EED motifs required for PRC2-dependent histone methylation. Journal of molecular biology 42 17997413
2017 Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED. PloS one 41 28072869
1999 HEED, the product of the human homolog of the murine eed gene, binds to the matrix protein of HIV-1. The Journal of biological chemistry 41 9880543
2022 Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies. Journal of medicinal chemistry 40 35352560
1993 N-ethyl-N-nitrosourea-induced prenatally lethal mutations define at least two complementation groups within the embryonic ectoderm development (eed) locus in mouse chromosome 7. Mammalian genome : official journal of the International Mammalian Genome Society 40 8358168
2021 Polycomb Repressive Complex 2 Modulation through the Development of EZH2-EED Interaction Inhibitors and EED Binders. Journal of medicinal chemistry 39 34351144
2019 The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation. Cell stem cell 39 30609396
2020 EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways. Science advances 36 32851157
2021 Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction. Journal of medicinal chemistry 35 34077206
2002 The Polycomb-group gene eed regulates thymocyte differentiation and suppresses the development of carcinogen-induced T-cell lymphomas. Oncogene 35 11803473
2021 Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer. Theranostics 32 34093859
1998 The murine Polycomb-group gene eed and its human orthologue: functional implications of evolutionary conservation. Genomics 32 9806832
2015 Polycomb protein EED is required for silencing of pluripotency genes upon ESC differentiation. Stem cell reviews and reports 31 25134795
2003 The protein phosphatase-1 (PP1) regulator, nuclear inhibitor of PP1 (NIPP1), interacts with the polycomb group protein, embryonic ectoderm development (EED), and functions as a transcriptional repressor. The Journal of biological chemistry 30 12788942
2008 Synergy of Eed and Tsix in the repression of Xist gene and X-chromosome inactivation. The EMBO journal 29 18511907
2022 Loss of microglial EED impairs synapse density, learning, and memory. Molecular psychiatry 28 35484239
2019 Polycomb Protein EED Regulates Neuronal Differentiation through Targeting SOX11 in Hippocampal Dentate Gyrus. Stem cell reports 28 31204298
2021 Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer. Aging 27 33882457
2007 Differences between homologous alleles of olfactory receptor genes require the Polycomb Group protein Eed. The Journal of cell biology 27 17954609
2018 Polycomb Protein Eed is Required for Neurogenesis and Cortical Injury Activation in the Subventricular Zone. Cerebral cortex (New York, N.Y. : 1991) 26 29415247
2016 Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America 25 27578866
2014 EED regulates epithelial-mesenchymal transition of cancer cells induced by TGF-β. Biochemical and biophysical research communications 25 25264103
2011 Eed/Sox2 regulatory loop controls ES cell self-renewal through histone methylation and acetylation. The EMBO journal 25 21540835
2017 SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. Bioorganic & medicinal chemistry letters 23 28254486
2021 Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression. Journal of medicinal chemistry 22 34613724
2021 Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase. Journal of medicinal chemistry 22 34807608
2021 An overview of the development of EED inhibitors to disable the PRC2 function. RSC medicinal chemistry 20 35224495
2022 EED is required for mouse primordial germ cell differentiation in the embryonic gonad. Developmental cell 19 35679863
2015 Inactivation of Eed impedes MLL-AF9-mediated leukemogenesis through Cdkn2a-dependent and Cdkn2a-independent mechanisms in a murine model. Experimental hematology 19 26118502
2020 Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal. ACS infectious diseases 18 32347704
2019 Three additional patients with EED-associated overgrowth: potential mutation hotspots identified? Journal of human genetics 17 30858506
2018 Novel de novo mutation affecting two adjacent aminoacids in the EED gene in a patient with Weaver syndrome. Journal of human genetics 17 29410511
1995 Physical localization of eed: a region of mouse chromosome 7 required for gastrulation. Genomics 17 7558026
2024 Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics. Drug discovery today 16 38642703
2022 Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs. European journal of medicinal chemistry 16 35093670
2019 Identification and Assessments of Novel and Potent Small-Molecule Inhibitors of EED-EZH2 Interaction of Polycomb Repressive Complex 2 by Computational Methods and Biological Evaluations. Chemical & pharmaceutical bulletin 16 31685780
2018 EED, a member of the polycomb group, is required for nephron differentiation and the maintenance of nephron progenitor cells. Development (Cambridge, England) 16 29945864
2021 Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase. Bioorganic & medicinal chemistry letters 15 33684441
2019 Discovery of selective activators of PRC2 mutant EED-I363M. Scientific reports 15 31024026
2016 Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency. Scientific reports 14 27432459
2024 A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies. European journal of cancer (Oxford, England : 1990) 12 39793445
2020 Binding Modes of Small-Molecule Inhibitors to the EED Pocket of PRC2. Chemphyschem : a European journal of chemical physics and physical chemistry 12 31816138
2022 Inhibition of polycomb repressive complex 2 by targeting EED protects against cisplatin-induced acute kidney injury. Journal of cellular and molecular medicine 11 35734954
2022 Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED-H3K27me3 Inhibitors for the Treatment of Lymphoma. Journal of medicinal chemistry 11 36580346
2007 Human Polycomb group EED protein negatively affects HIV-1 assembly and release. Retrovirology 10 17547741
2023 Inhibition of EED activity enhances cell survival of female germline stem cell and improves the oocytes production during oogenesis in vitro. Open biology 9 36695089
2023 Gene-repressing epigenetic reader EED unexpectedly enhances cyclinD1 gene activation. Molecular therapy. Nucleic acids 9 36923952
2017 Allosteric Inactivation of Polycomb Repressive Complex 2 (PRC2) by Inhibiting Its Adapter Protein: Embryonic Ectodomain Development (EED). Journal of medicinal chemistry 9 28256832
2023 Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models. British journal of cancer 8 37474721
2022 Preclinical pharmacokinetics and metabolism of MAK683, a clinical stage selective oral embryonic ectoderm development (EED) inhibitor for cancer treatment. Xenobiotica; the fate of foreign compounds in biological systems 8 34761729
2022 Gut biomolecules (I-FABP, TFF3 and lipocalin-2) are associated with linear growth and biomarkers of environmental enteric dysfunction (EED) in Bangladeshi children. Scientific reports 8 35974137
2013 MicroRNA-323-3p regulates the activity of polycomb repressive complex 2 (PRC2) via targeting the mRNA of embryonic ectoderm development (Eed) gene in mouse embryonic stem cells. The Journal of biological chemistry 8 23821546
2003 SETting the stage. Eed-Enx1 leaves an epigenetic signature on the inactive X chromosome. Developmental cell 8 12689584

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