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Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

Daniel Bsteh1,2,3,4, Hagar F Moussa1,2,5, Georg Michlits1,2,6

  • 1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.

Nature Communications
|December 9, 2023
PubMed

Insights

The cohesin regulator PDS5A is crucial for Polycomb-mediated gene silencing by organizing 3D genome structure. Its absence disrupts Polycomb loops, leading to gene derepression and highlighting the importance of genome architecture in epigenetic regulation.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Genomics

Background:

  • Polycomb Repressive Complexes (PRC1, PRC2) are key epigenetic regulators of transcriptional gene silencing.
  • PRC1 and PRC2 target specific genes and catalyze repressive histone modifications.
  • The role of long-range genomic interactions in Polycomb-mediated silencing is not well understood.

Purpose of the Study:

  • To investigate the link between Polycomb-mediated transcriptional silencing and 3D genome organization.
  • To identify factors that connect these two processes using a functional genomics screen.

Main Methods:

  • CRISPR screening in mouse embryonic stem cells.
  • Analysis of gene expression and histone modifications.
  • Assessment of cohesin dynamics and 3D genome structure.

Main Results:

  • PDS5A, a cohesin regulator, was identified as a key link between Polycomb silencing and genome organization.
  • PDS5A deletion led to impaired cohesin unloading and derepression of PRC1/PRC2 target genes.
  • Aberrant cohesin activity and ectopic insulation sites disrupted ultra-long Polycomb loops, essential for robust silencing.

Conclusions:

  • PDS5A is critical for maintaining cohesin-dependent genome architecture required for Polycomb gene silencing.
  • Disruption of Polycomb loops by aberrant cohesin activity impairs robust gene silencing.
  • Cohesin-dependent genome organization is vital for effective Polycomb regulation.

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