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Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

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  • Daniel Bsteh

    (Vienna BioCenter (VBC)
    Doctoral School of the University of Vienna and Medical University of Vienna
    University of Southern California
    University of Southern California)

  • Hagar F. Moussa

    (Vienna BioCenter (VBC)
    Doctoral School of the University of Vienna and Medical University of Vienna
    Boston University)

  • Georg Michlits

    (Vienna BioCenter (VBC)
    Doctoral School of the University of Vienna and Medical University of Vienna
    JLP Health GmbH)

  • Ramesh Yelagandula

    (Vienna BioCenter (VBC)
    Centre for DNA Fingerprinting and Diagnostics (CDFD), Uppal)

  • Jingkui Wang

    (Vienna BioCenter (VBC)
    Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC))

  • Ulrich Elling

    (Vienna BioCenter (VBC))

  • Oliver Bell

    (Vienna BioCenter (VBC)
    University of Southern California)

Abstract

Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional gene silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. Additionally, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we found that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of a subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not linked to loss of Polycomb chromatin domains. Instead, PDS5A removal causes aberrant cohesin activity leading to ectopic insulation sites, which disrupt the formation of ultra-long Polycomb loops. We show that these loops are important for robust silencing at a subset of PRC1/PRC2 target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.

Suggested Citation

  • Daniel Bsteh & Hagar F. Moussa & Georg Michlits & Ramesh Yelagandula & Jingkui Wang & Ulrich Elling & Oliver Bell, 2023. "Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43869-w
    DOI: 10.1038/s41467-023-43869-w
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