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G-tract RNA removes Polycomb repressive complex 2 from genes.

Manuel Beltran1, Manuel Tavares1, Neil Justin2

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|September 25, 2019
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G-tract RNA, particularly G-quadruplex structures in precursor mRNA, removes Polycomb repressive complex 2 (PRC2) from genes. This mechanism reactivates tumor suppressor genes and offers a way to reverse aberrant PRC2 activity.

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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Polycomb repressive complex 2 (PRC2) is crucial for gene repression but can be aberrantly recruited in cancer.
  • Understanding PRC2 removal mechanisms is key for reversing detrimental gene silencing.

Purpose of the Study:

  • To investigate how PRC2 is removed from genes.
  • To identify mechanisms for targeted reversal of aberrant PRC2 recruitment.

Main Methods:

  • Studied PRC2 binding to G-tract RNA and G-quadruplex structures in nascent pre-mRNA.
  • Observed PRC2 transfer from chromatin to pre-mRNA during gene activation in human and mouse cells.
  • Targeted G-tract RNA to the CDKN2A gene in malignant rhabdoid tumor cells.

Main Results:

  • PRC2 preferentially binds G tracts in pre-mRNA, especially G-quadruplex structures.
  • G-quadruplex RNA can evict the PRC2 catalytic core from nucleosomes.
  • Chromatin-associated G-tract RNA mediates PRC2 removal upon gene activation, leading to H3K27me3 depletion.
  • Targeting G-tract RNA to CDKN2A reactivated the gene and induced senescence in cancer cells.

Conclusions:

  • Pre-mRNA, via G-tract RNA, plays a role in evicting PRC2 during gene activation.
  • This mechanism provides a means for selective PRC2 removal from specific genes.
  • G-tract RNA represents a potential therapeutic target for reactivating silenced tumor suppressor genes.