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SKP1A bound to Polycomb-silenced genes mediates degradation of PRC2 and preconditions their activation

Takashi Kondo1, Shinsuke Ito1, Junichiro Takano1

  • 1Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Molecular Cell
|August 26, 2025
PubMed

Insights

SKP1A links Polycomb gene regulation to protein degradation. It removes EED from PRC2, preconditioning target genes for activation and enabling reversible gene silencing.

Area of Science:

  • Epigenetics and Gene Regulation
  • Molecular Biology
  • Developmental Biology

Background:

  • Polycomb group (PcG) proteins typically repress developmental genes but can also activate them through unknown mechanisms.
  • Understanding the interplay between PcG-mediated gene silencing and activation is crucial for developmental processes.

Purpose of the Study:

  • To investigate the role of SKP1A in linking Polycomb group (PcG) dependent gene regulation to ubiquitin proteasomal degradation.
  • To elucidate the mechanism by which PcG proteins contribute to gene activation.

Main Methods:

  • Utilized differentiating mouse embryonic stem cells and developing mouse embryo midbrains.
  • Investigated the interaction of SKP1A with Polycomb Repressive Complex 2 (PRC2) components.
  • Analyzed the impact of SKP1A on EED protein levels and gene promoter accessibility.

Main Results:

  • SKP1A, a component of SCF ubiquitin ligases and PCGF1-PRC1, was found to mediate the connection between PcG gene regulation and proteasomal degradation.
  • SKP1A facilitates the removal of EED, a core PRC2 component, from PcG target gene promoters via proteasomal degradation.
  • This degradation sensitizes PcG target genes for subsequent activation.

Conclusions:

  • SKP1A plays a novel role in preconditioning PcG target genes for activation by degrading PRC2.
  • SKP1A-containing PCGF1-PRC1 complexes may enable reversible Polycomb-mediated gene silencing.
  • This mechanism contributes to the spatiotemporal regulation of target genes during development.
Keywords:
PRC1PRC2Polycombgene regulationproteasomeubiquitination

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