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

Nmezi, B.; Rodriguez Bey, G.; Oranburg, T. D.; Dudnyk, K.; Lardo, S. M.; Herdman, N.; Jacko, A.; Rubio, S.; Loeza-Alcocer, E.; Kofler, J.; Kim, D.; Rankin, J.; Kivuva, E.; Gutowski, N.; Schon, K.; van den Ameele, J.; Chinnery, P. F.; Sousa, S. B.; Palavra, F.; Toro, C.; Pinto, E. Vairo F.; Saute, J.; Pan, L.; Alturkustani, M.; Hammond, R.; Gros-Louis, F.; Gold, M. S.; Park, Y.; Bernard, G.; Raininko, R.; Zhou, J.; Hainer, S. J.; Padiath, Q. S.

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

Authors

Nmezi, B.

Rodriguez Bey, G.

Oranburg, T. D.

Dudnyk, K.

Lardo, S. M.

Herdman, N.

Jacko, A.

Rubio, S.

Loeza-Alcocer, E.

Kofler, J.

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Issue Date

2025-02-05

Type

Journal Article

Language

eng

Keywords

*Lamin Type B/metabolism/genetics , Humans , Animals , *Oligodendroglia/metabolism/pathology , Mice , CCCTC-Binding Factor/metabolism/genetics , Silencer Elements, Transcriptional/genetics , Pelizaeus-Merzbacher Disease/genetics/metabolism/pathology , Chromatin/metabolism/genetics , Binding Sites , Male , Gene Duplication , Female

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.

Citation

Nmezi B, Rodriguez Bey G, Oranburg TD, Dudnyk K, Lardo SM, Herdman N, et al. An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants. Nature communications. 2025;16(1):1373.

Publisher

Nature

License

Journal

Nature communications