Polycomb repressive complex 2 subunit EED (EED)

Polycomb repressive complex 2 subunit EED is a core component of the Polycomb Repressive Complex 2 (PRC2), an essential epigenetic regulator responsible for the trimethylation of histone H3 at lysine 27 (H3K27me3). EED functions as a molecular scaffold and an allosteric activator within the complex; it contains a WD40 repeat domain that specifically recognizes and binds to existing H3K27me3 marks. This binding event induces a conformational change in the catalytic subunit, Enhancer of zeste homolog 2 (EZH2), significantly enhancing its methyltransferase activity and allowing for the propagation of repressive chromatin states across the genome. In various malignancies, including lymphomas and certain solid tumors, PRC2 is frequently overactive or mutated, leading to the silencing of critical tumor suppressor genes and promoting oncogenesis. Therapeutic strategies targeting EED focus on allosteric inhibitors that occupy its H3K27me3-binding pocket, thereby disrupting the allosteric activation of the entire PRC2 complex. These inhibitors offer a distinct mechanism of action compared to traditional SAM-competitive EZH2 inhibitors and have shown potential in overcoming resistance in PRC2-dependent cancers.

Other names

Embryonic ectoderm developmentWD repeat-containing protein EEDWAIT1HEED

Allosteric inhibition of the Polycomb Repressive Complex 2 (PRC2) by binding to the H3K27me3-recognition pocket of EED, preventing the allosteric activation of the EZH2 catalytic subunit and disrupting the propagation of repressive histone marks.