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Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin

Author

Listed:
  • Felix D. Weiss

    (Imperial College London
    University of Bonn)

  • Lesly Calderon

    (Imperial College London
    Research Institute of Molecular Pathology)

  • Yi-Fang Wang

    (Imperial College London)

  • Radina Georgieva

    (Imperial College London
    Imperial College London)

  • Ya Guo

    (Imperial College London
    Shanghai Jiao Tong University)

  • Nevena Cvetesic

    (Imperial College London)

  • Maninder Kaur

    (The Children’s Hospital of Philadelphia)

  • Gopuraja Dharmalingam

    (Imperial College London)

  • Ian D. Krantz

    (The Children’s Hospital of Philadelphia
    The Perelman School of Medicine at The University of Pennsylvania
    The Children’s Hospital of Philadelphia)

  • Boris Lenhard

    (Imperial College London
    University of Bergen)

  • Amanda G. Fisher

    (Imperial College London)

  • Matthias Merkenschlager

    (Imperial College London)

Abstract

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.

Suggested Citation

  • Felix D. Weiss & Lesly Calderon & Yi-Fang Wang & Radina Georgieva & Ya Guo & Nevena Cvetesic & Maninder Kaur & Gopuraja Dharmalingam & Ian D. Krantz & Boris Lenhard & Amanda G. Fisher & Matthias Merke, 2021. "Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23141-9
    DOI: 10.1038/s41467-021-23141-9
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