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

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-05
DOI
https://doi.org/10.1038/s41467-025-56378-9
Citations
5
Primary Topic
Nuclear Structure and Function
Type
article
Field-Weighted Citation Impact
4.03

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article

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

Julia Kofler, Talia DeFrancesco Oranburg, Sarah J. Hainer, Emma Kivuva et al.
5 citations
Nature Communications
Nuclear Structure and Function
4.03
article

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

Julia Kofler, Talia DeFrancesco Oranburg, Sarah J. Hainer, Emma Kivuva, Geneviève Bernard, Katherine R. Schon, Nicholas J. Gutowski, Patrick Francis Chinnery, Camilo Toro, Robert Hammond, Filipe Palavra, Bruce Nmezi, Dongkyeong Kim, Filippo Pinto e Vairo, Nathan Herdman, Raili Raininko, François Gros‐Louis, Kseniia Dudnyk, Jelle van den Ameele, Lisa Pan, Michael Gold, Jian Zhou, Quasar Saleem Padiath, Murad Alturkustani, Yungki Park, Santana M. Lardo, Guillermo Rodríguez Bey, Jonas Alex Morales Saute, Sandy Rubio, Anastasia M. Jacko, Sérgio B. Sousa, Julia Rankin, Emanuel Loeza-Alcocer
article en
5 citations

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.

Nature CommunicationsVol. 16(1)
Uppsala University (SE), Western University (CA), National Institutes of Health (US), Universidade Federal do Rio Grande do Sul (BR), Mayo Clinic (US), University of Pittsburgh (US), King Abdulaziz University (SA), University of Cambridge (GB), London Health Sciences Centre (CA), Royal Devon and Exeter Hospital (GB), McGill University Health Centre (CA), Hospitais da Universidade de Coimbra (PT), Cambridge University Hospitals NHS Foundation Trust (GB), National Human Genome Research Institute (US), Hospital de Clínicas de Porto Alegre (BR), Mayo Clinic in Florida (US), Io Therapeutics (United States) (US), Université Laval (CA), McGill University (CA), University at Buffalo, State University of New York (US), University of Coimbra (PT), MRC Mitochondrial Biology Unit (GB), The University of Texas Southwestern Medical Center (US)
University of Pittsburgh, National Institute for Health and Care Research, National Institutes of Health, Center for Research Computing, University of Pittsburgh, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé, Medical Research Council, NIHR Cambridge Biomedical Research Centre
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Openalex Percentile: Top 7%
Nuclear Structure and Function
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