Embryonic ectoderm development protein (EED) (EED)

Embryonic ectoderm development (EED) protein is a fundamental scaffolding component of the Polycomb Repressive Complex 2 (PRC2), an epigenetic machinery responsible for the trimethylation of histone H3 at lysine 27 (H3K27me3) (UniProt P48332; Margueron & Reinberg, Nature 2011). This modification is a critical repressive mark that leads to chromatin condensation and gene silencing, playing a vital role in maintaining cellular identity and regulating embryonic development (UniProt P48332). EED functions by binding to pre-existing H3K27me3 marks via its WD40 repeat domain, which induces a conformational change that allosterically activates the methyltransferase activity of EZH2, the catalytic subunit of PRC2 (Qi et al., Nature Chemical Biology 2017). In many cancers, PRC2 is overactive or mutated, leading to the aberrant silencing of tumor suppressor genes and promoting oncogenesis (He et al., Journal of Hematology & Oncology 2021). Pharmacological targeting of EED focuses on small-molecule allosteric inhibitors that occupy its H3K27me3-binding pocket, thereby disrupting the PRC2 activation loop and reducing global H3K27me3 levels (Qi et al., Nature Chemical Biology 2017). These inhibitors, such as MAK683 and APG-5918, are currently under clinical investigation for treating various malignancies, including lymphomas and solid tumors (ClinicalTrials.gov NCT02900651).

Other names

EEDHEEDWAIT1Polycomb protein EEDWD repeat-containing protein EED

Allosteric inhibition of Polycomb Repressive Complex 2 (PRC2) by binding to the H3K27me3-binding pocket of EED, which prevents the allosteric activation of the catalytic subunit EZH2 (Qi et al., Nature Chemical Biology 2017).