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An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

Author

Listed:
  • Bruce Nmezi

    (University of Pittsburgh)

  • Guillermo Rodriguez Bey

    (University of Pittsburgh)

  • Talia DeFrancesco Oranburg

    (University of Pittsburgh)

  • Kseniia Dudnyk

    (University of Texas Southwestern Medical Center)

  • Santana M. Lardo

    (University of Pittsburgh)

  • Nathan Herdman

    (University of Pittsburgh)

  • Anastasia Jacko

    (University of Pittsburgh)

  • Sandy Rubio

    (University of Pittsburgh)

  • Emanuel Loeza-Alcocer

    (University of Pittsburgh)

  • Julia Kofler

    (University of Pittsburgh)

  • Dongkyeong Kim

    (State University of New York at Buffalo
    Epitor Therapeutics)

  • Julia Rankin

    (Royal Devon University Hospital)

  • Emma Kivuva

    (Royal Devon University Hospital)

  • Nicholas Gutowski

    (Royal Devon University Hospital)

  • Katherine Schon

    (Cambridge Biomedical Campus
    University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Jelle Ameele

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Patrick F. Chinnery

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Sérgio B. Sousa

    (Centro Hospitalar e Universitário de Coimbra
    Universidade de Coimbra
    Clinical Academic Center of Coimbra (CACC))

  • Filipe Palavra

    (Clinical Academic Center of Coimbra (CACC)
    Centro Hospitalar Universitário de Coimbra
    University of Coimbra)

  • Camilo Toro

    (National Institutes of Health)

  • Filippo Pinto e Vairo

    (Mayo Clinic
    Mayo Clinic)

  • Jonas Saute

    (Hospital de Clínicas de Porto Alegre (HCPA)
    Universidade Federal do Rio Grande do Sul)

  • Lisa Pan

    (University of Pittsburgh)

  • Murad Alturkustani

    (King Abdulaziz University)

  • Robert Hammond

    (Western University and London Health Sciences Centre)

  • Francois Gros-Louis

    (Laval University
    Laval University)

  • Michael S. Gold

    (University of Pittsburgh)

  • Yungki Park

    (State University of New York at Buffalo)

  • Geneviève Bernard

    (McGill University
    McGill University Health Centre
    Research Institute of the McGill University Health Centre)

  • Raili Raininko

    (Uppsala University)

  • Jian Zhou

    (University of Texas Southwestern Medical Center)

  • Sarah J. Hainer

    (University of Pittsburgh)

  • Quasar S. Padiath

    (University of Pittsburgh
    University of Pittsburgh)

Abstract

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR edited cell lines and mouse models, we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving LMNB1 and the recruitment of the PRC2 transcriptional repressor complex. Loss of the silencer element in ADLD identifies a role for non-coding regulatory elements in tissue specificity and disease causation.

Suggested Citation

  • Bruce Nmezi & Guillermo Rodriguez Bey & Talia DeFrancesco Oranburg & Kseniia Dudnyk & Santana M. Lardo & Nathan Herdman & Anastasia Jacko & Sandy Rubio & Emanuel Loeza-Alcocer & Julia Kofler & Dongkye, 2025. "An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56378-9
    DOI: 10.1038/s41467-025-56378-9
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    References listed on IDEAS

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