Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications

Area of Science:

• Epigenetics
• Molecular Biology
• Structural Biology

Background:

• Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator controlling gene expression via histone H3 lysine 27 trimethylation (H3K27me3).
• PRC2 function is influenced by cofactor interactions and crosstalk with other histone modifications.
• H3K4me3 and H3K36me3, marks of active transcription, are known inhibitors of PRC2, but the mechanisms remain unclear.

Approach:

• Cryo-electron microscopy (cryo-EM) was employed to visualize PRC2 in complex with modified histone H3 tails.
• Structural analysis elucidated the molecular interactions between PRC2 and H3K4me3/H3K36me3 modifications.
• Biochemical assays were used to assess the functional impact of these interactions and cofactor JARID2.

Key Points:

• H3K36me3 modification on the histone H3 tail hinders PRC2's active site engagement with chromatin.
• H3K4me3 modification binds to the EED subunit's allosteric site, antagonizing PRC2 activation and H3K27me3 spreading.
• The distinct localization of H3K4me3 and H3K36me3 on the H3 tail targets crucial steps for H3K27me3.
• The cofactor JARID2 was shown to modulate PRC2 activity in the context of these inhibitory histone marks.

Conclusions:

• Structural and functional data reveal how H3K4me3 and H3K36me3 inhibit PRC2-mediated gene silencing.
• These findings provide mechanistic insights into the antagonistic crosstalk between active and repressive epigenetic marks.
• Understanding these regulatory mechanisms is crucial for deciphering embryonic development and cell identity maintenance.