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<p>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 (<i>LMNB1</i>) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry <i>LMNB1</i> 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 <i>LMNB1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月5日

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  • 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 van den 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,
  • Quasar S. Padiath

摘要

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.