EED
| | | [1]
|---|---| [2]
| Full Name | Embryonic Ectoderm Development | [3]
| Gene Symbol | EED | [4]
| Aliases | WAIT1, HEED, ESC | [5]
| Chromosome | 11q14.2 | [6]
| Gene Type | Protein-coding | [7]
| OMIM | 605984 | [8]
| UniProt | O75530 |
| HGNC | 3188 |
| Entrez Gene | 8726 |
| Ensembl | ENSG00000074266 |
EED is a human gene. Variants in EED have been implicated in Alzheimer's Disease, Huntington's Disease, Parkinson's Disease. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
EED (Embryonic Ectoderm Development) encodes a core scaffolding subunit of Polycomb Repressive Complex 2 (PRC2), the multisubunit complex responsible for trimethylation of histone H3 at lysine 27 (H3K27me3).[1] EED functions as the allosteric activator of PRC2 by binding existing H3K27me3 marks through its WD40 repeat domain, creating a positive feedback loop that enables spreading of this repressive histone modification across chromatin.[2] In the nervous system, EED is essential for neural fate specification, maintenance of neuronal subtype identity, and repression of non-neuronal transcriptional programs. Disruption of EED-PRC2 function contributes to Alzheimer's disease, Parkinson's disease, and Huntington's disease.
EED is a WD40 repeat protein that forms a seven-bladed beta-propeller structure. It associates with EZH2 (or EZH1) and SUZ12 to form the catalytically active PRC2 core complex. EED performs two critical functions: structural scaffolding of the PRC2 complex and allosteric activation of the methyltransferase.
EED's aromatic cage (formed by residues F97, Y148, Y153, Y365 in its WD40 domain) recognizes and binds H3K27me3 on adjacent nucleosomes. This binding event induces a conformational change that is transmitted through the EED-EZH2 interface to the SET domain of EZH2, stimulating methyltransferase activity approximately 7-fold.[2] This read-write mechanism enables PRC2 to propagate H3K27me3 along chromatin fibers, spreading repressive domains from nucleation sites.
EED interacts with EZH2 through its WD40 domain (binding the EZH2 EED-binding domain, EBD) and with SUZ12 through additional contacts. Without EED, EZH2 cannot fold properly and is rapidly degraded, making EED essential for PRC2 stability and catalytic function.[3]
During neural development, EED-PRC2 silences mesodermal and endodermal lineage genes, restricting progenitor cells to neural fates. EED also controls the temporal switch from neurogenesis to gliogenesis by progressively silencing proneural transcription factors. Conditional Eed deletion in neural progenitors leads to premature neurogenesis, ectopic gene expression, and postnatal lethality.[4]
In postmitotic neurons, EED-PRC2 maintains cell-type-specific transcriptional programs by silencing alternative neuronal subtype genes. Loss of EED in mature neurons leads to gradual derepression of inappropriate gene programs and progressive neurodegeneration.[5]
H3K27me3 levels are globally altered in Alzheimer's disease brains, with both gains and losses at specific loci. EED expression declines in AD hippocampal neurons, reducing PRC2 activity and permitting derepression of normally silenced inflammatory and cell cycle genes. Loss of H3K27me3 at tau kinase genes may contribute to MAPT hyperphosphorylation.[6]
PRC2 dysfunction is a prominent feature of Huntington's disease. Mutant huntingtin interacts with PRC2 components and redirects the complex to ectopic genomic loci in striatal neurons. This leads to inappropriate H3K27me3 deposition at neuronal identity genes while depleting H3K27me3 from Polycomb targets, causing a dual gain-loss epigenetic catastrophe.[5]
In Parkinson's disease, alpha-synuclein aggregation sequesters EED-PRC2 from the nucleus, reducing nuclear H3K27me3. Dopaminergic neuron-specific EED targets, including genes controlling catecholamine biosynthesis and axonal maintenance, become derepressed inappropriately.[7]
Heterozygous missense mutations in EED cause Cohen-Gibson syndrome, a Weaver-like overgrowth disorder with intellectual disability, characteristic facial features, and advanced bone age. These mutations typically cluster in the H3K27me3-binding aromatic cage, disrupting allosteric activation.[8]
EED is broadly expressed throughout the central nervous system with enrichment in neural progenitor zones during development. In the adult brain, EED maintains moderate expression in cortical pyramidal neurons, hippocampal neurons, striatal medium spiny neurons, and dopaminergic neurons of the substantia nigra. Expression gradually declines with aging, particularly in vulnerable neuronal populations.
| Variant | Type | Association | Reference |
|---|---|---|---|
| R236T | Missense | Cohen-Gibson syndrome/NDD | Cohen et al., 2015 |
| H258Y | Missense | PRC2 gain-of-function/overgrowth | Cooney et al., 2017 |
| EED promoter methylation | Epigenetic | Reduced expression in aging brain | Nativio et al., 2018 |
Montgomery et al. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation (2005). 2005. ↩︎
Hirabayashi et al. Polycomb limits the neurogenic competence of neural precursor cells (2009). 2009. ↩︎
von Schimmelmann et al. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration (2016). 2016. ↩︎
Nativio et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease (2018). 2018. ↩︎
Chatoo et al. The polycomb group gene Bmi1 regulates antioxidant defenses in neurons (2009). 2009. ↩︎
Cohen et al. A novel mutation in EED associated with overgrowth (2015). 2015. ↩︎
Qi et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED (2017). 2017. ↩︎
Pereira et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex (2010). 2010. ↩︎