Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for gene silencing.
• It catalyzes histone H3K27 trimethylation (H3K27me3), a key epigenetic mark.
• Dysregulation of PRC2 is implicated in various cancers.

Purpose of the Study:

• To elucidate the structural mechanisms of PRC2 activity.
• To visualize the interaction of PRC2 with inhibitory peptides and cofactors.
• To understand the allosteric regulation of PRC2.

Main Methods:

• X-ray crystallography was used to determine the structure of the PRC2 complex.
• The study utilized a 170 kDa active PRC2 complex from Chaetomium thermophilum.
• The structures were determined in both basal and stimulated states, bound to peptides and cofactors.

Main Results:

• Crystal structures of active PRC2 in basal and stimulated states were obtained.
• The structures reveal the interaction of Ezh2, Eed, and Suz12(VEFS).
• A mobile Ezh2 motif was identified that allosterically regulates the active site in response to stimulation.

Conclusions:

• The study provides unprecedented structural insights into PRC2 function.
• Understanding PRC2 regulation offers potential therapeutic targets for cancer.
• The findings highlight the structural basis for allosteric control in epigenetic modifiers.