Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Biology

Background:

• Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator responsible for gene silencing via histone H3 lysine 27 trimethylation (H3K27me3).
• A specific mutation, H3K27M, in histone H3 is associated with aggressive pediatric brain tumors and leads to a global reduction in H3K27me3.
• The mechanism by which H3K27M causes PRC2 inhibition and subsequent H3K27me3 depletion remains incompletely understood.

Purpose of the Study:

• To elucidate the structural basis of H3K27M-mediated inhibition of human PRC2.
• To understand how PRC2 recognizes and propagates repressive histone marks like H3K27me3.

Main Methods:

• X-ray crystallography was employed to determine the structure of human PRC2 in complex with an H3K27M inhibitory peptide.
• Biochemical binding studies were performed to analyze the interactions between PRC2, H3K27M, and H3K27me3.

Main Results:

• The crystal structure reveals that the H3K27M mutation directly binds to the active site of the PRC2 SET domain, with methionine occupying the lysine-binding pocket.
• This structural insight provides a mechanistic explanation for the oncogenic inhibition of PRC2 by H3K27M.
• The study also demonstrates that binding of H3K27me3 to the EED subunit allosterically enhances the catalytic activity of the SET domain.

Conclusions:

• The H3K27M mutation oncogenically inhibits PRC2 by directly competing with the substrate lysine at the SET domain active site.
• PRC2 activity is positively regulated by its own repressive mark, H3K27me3, through allosteric enhancement, promoting the spread of gene silencing.
• These findings offer critical insights into the epigenetic dysregulation in pediatric brain cancers and the regulation of histone methylation.