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

Bruce Nmezi, Guillermo Rodriguez Bey, Talia DeFrancesco Oranburg, Kseniia Dudnyk, Santana M. Lardo, Nathan Herdman, Anastasia Jacko, Sandy Rubio, Emanuel Loeza-Alcocer, Julia Kofler, Dongkyeong Kim, Julia Rankin, Emma Kivuva, Nicholas Gutowski, Katherine Schon, Jelle Ameele, Patrick F. Chinnery, Sérgio B. Sousa, Filipe Palavra, Camilo Toro, Filippo Pinto e Vairo, Jonas Saute, Lisa Pan, Murad Alturkustani, Robert Hammond, Francois Gros-Louis, Michael S. Gold, Yungki Park, Geneviève Bernard, Raili Raininko, Jian Zhou, Sarah J. Hainer and Quasar S. Padiath ()
Additional contact information
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
Julia Rankin: Royal Devon University Hospital
Emma Kivuva: Royal Devon University Hospital
Nicholas Gutowski: Royal Devon University Hospital
Katherine Schon: Cambridge Biomedical Campus
Jelle Ameele: Cambridge Biomedical Campus
Patrick F. Chinnery: Cambridge Biomedical Campus
Sérgio B. Sousa: Centro Hospitalar e Universitário de Coimbra
Filipe Palavra: Clinical Academic Center of Coimbra (CACC)
Camilo Toro: National Institutes of Health
Filippo Pinto e Vairo: Mayo Clinic
Jonas Saute: Hospital de Clínicas de Porto Alegre (HCPA)
Lisa Pan: University of Pittsburgh
Murad Alturkustani: King Abdulaziz University
Robert Hammond: Western University and London Health Sciences Centre
Francois Gros-Louis: Laval University
Michael S. Gold: University of Pittsburgh
Yungki Park: State University of New York at Buffalo
Geneviève Bernard: McGill University
Raili Raininko: Uppsala University
Jian Zhou: University of Texas Southwestern Medical Center
Sarah J. Hainer: University of Pittsburgh
Quasar S. Padiath: University of Pittsburgh

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56378-9

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