Role of the polycomb protein EED in the propagation of repressive histone marks

Abstract

Summary Polycomb Group (PcG) proteins play an essential role in the epigenetic maintenance of repressive chromatin states. The gene silencing activity of the Polycomb Repressive Complex 2 (PRC2) depends on its ability to tri-methylate lysine 27 of histone H3 (H3K27) via the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: Suz12 and Eed. We show that the C-terminal domain of Eed specifically binds to histone tails carrying tri-methyl lysine residues associated with repressive chromatin marks and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in Eed that prevent it from recognising repressive trimethyl-lysine marks abolish activation of PRC2 in vitro and, in Drosophila, reduces global methylation and disrupts development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…During replication, parental histones re-associate locally with newly synthesized DNA in budding yeast (22). H3K27me3 marks appear to propagate via replication in Drosophila (23). However, whether this mechanism is conserved in vertebrates, is uncertain.…”

EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms

“…1,2,6 In addition, EED binds to trimethylated H3K27 (H3K27me3) through the so-called 'aromatic cage' composed of three aromatic amino acids (Phe97, Trp364 and Tyr365) to activate PRC2. 1,7 A previous report demonstrated that PRC2 complexes possessing an aromatic-cage mutation in EED show severely reduced enzymatic activities in the presence of H3K27me3 peptides. 7 EED haploinsufficiency (Leu196Pro) in mice leads spontaneously to a myeloproliferative disorder, 8 and exposure of hypomorphic (Ile193Asn) homozygotes to genotoxic stresses gives rise to tumorigenesis.…”

“…1,7 A previous report demonstrated that PRC2 complexes possessing an aromatic-cage mutation in EED show severely reduced enzymatic activities in the presence of H3K27me3 peptides. 7 EED haploinsufficiency (Leu196Pro) in mice leads spontaneously to a myeloproliferative disorder, 8 and exposure of hypomorphic (Ile193Asn) homozygotes to genotoxic stresses gives rise to tumorigenesis. 8,9 These findings strongly suggest that dysfunction of EED might be involved in the pathogenesis of myeloid disorders.…”

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

“…For example, H3K27 trimethylation, is both catalyzed and recognized by the PRC2 methyltransferase complex (Hansen et al, 2008). The PRC2 subunit, EED, binds H3K27me3 both to recruit the PRC2 complex and to allosterically activate its methyltransferase activity, setting up a positive feedback loop to propagate the epigenetic mark through cell division without need for sequence specific factors (Margueron et al, 2009). In this context, many chromatin modifications are not in fact epigenetic.…”