Goldilocks meets Polycomb.

Area of Science:

• Epigenetics and Gene Regulation
• Chromatin Biology
• Developmental Biology

Background:

• The Polycomb system is essential for maintaining gene repression during cellular differentiation.
• Key Polycomb repressive mechanisms include H3K27 trimethylation (H3K27me3) by PRC2, H2A monoubiquitylation (H2Aub1) by ncPRC1, and chromatin compaction by cPRC1.
• The role of PR-DUB in deubiquitylating H2Aub1 has been puzzling in the context of Polycomb repression.

Purpose of the Study:

• To resolve the paradox of PR-DUB's requirement in Polycomb repression.
• To investigate the precise role of H2Aub1 levels in chromatin structure and gene expression.
• To elucidate the interplay between PR-DUB, PRC1 activity, and chromatin compaction.

Main Methods:

• Utilized *Drosophila* models to study Polycomb repression mechanisms.
• Assessed chromatin accessibility and gene expression in the absence of PR-DUB activity.
• Investigated the effects of altering PRC1 E3 ubiquitin ligase activity and chromatin compaction activity.

Main Results:

• High H2Aub1 levels in PR-DUB-deficient *Drosophila* promote open chromatin and gene expression, despite normal H3K27me3 and PRC binding.
• Gene repression is restored upon simultaneous loss of PRC1 E3 ubiquitin ligase activity.
• Restored repression depends on PRC1's chromatin compaction activity, not its enzymatic ligase function.

Conclusions:

• PR-DUB is critical for fine-tuning H2Aub1 levels, which is necessary for Polycomb-mediated gene silencing.
• Optimal H2Aub1 levels enable chromatin compaction mediated by canonical PRC1.
• This study clarifies a key regulatory step in Polycomb repression, linking deubiquitylation to chromatin structure and gene silencing.