An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants
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...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56378-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Bruce Nmezi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b25dc992b25a4965b932bbcbaa7868f2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b25dc992b25a4965b932bbcbaa7868f22025-02-09T12:45:30ZengNature PortfolioNature Communications2041-17232025-02-0116112110.1038/s41467-025-56378-9An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variantsBruce Nmezi0Guillermo Rodriguez Bey1Talia DeFrancesco Oranburg2Kseniia Dudnyk3Santana M. Lardo4Nathan Herdman5Anastasia Jacko6Sandy Rubio7Emanuel Loeza-Alcocer8Julia Kofler9Dongkyeong Kim10Julia Rankin11Emma Kivuva12Nicholas Gutowski13Katherine Schon14Jelle van den Ameele15Patrick F. Chinnery16Sérgio B. Sousa17Filipe Palavra18Camilo Toro19Filippo Pinto e Vairo20Jonas Saute21Lisa Pan22Murad Alturkustani23Robert Hammond24Francois Gros-Louis25Michael S. Gold26Yungki Park27Geneviève Bernard28Raili Raininko29Jian Zhou30Sarah J. Hainer31Quasar S. Padiath32Dept of Human Genetics, School of Public Health, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghLyda Hill Department of Bioinformatics, University of Texas Southwestern Medical CenterDept. of Biological Sciences, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghDept. of Neurobiology, School of Medicine, University of PittsburghDept. of Neuropathology, School of Medicine, University of PittsburghInstitute for Myelin and Glia Exploration, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at BuffaloDept. of Clinical Genetics, Royal Devon University HospitalDept. of Clinical Genetics, Royal Devon University HospitalDept. of Neurology, Royal Devon University HospitalDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusDepartment of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical CampusMedical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de CoimbraClinical Academic Center of Coimbra (CACC)NIH Undiagnosed Diseases Program, National Human Genome Institute, National Institutes of HealthCenter for Individualized Medicine, Mayo ClinicMedical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA)Dept of Human Genetics, School of Public Health, University of PittsburghDepartment of Pathology, King Abdulaziz UniversityDepartments of Pathology and Clinical Neurological Sciences, Western University and London Health Sciences CentreDepartment of Surgery, Faculty of Medicine, Laval UniversityDept. of Neurobiology, School of Medicine, University of PittsburghInstitute for Myelin and Glia Exploration, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at BuffaloDepartment of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill UniversityDepartment of Radiology, Uppsala UniversityLyda Hill Department of Bioinformatics, University of Texas Southwestern Medical CenterDept. of Biological Sciences, University of PittsburghDept of Human Genetics, School of Public Health, University of PittsburghAbstract 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.https://doi.org/10.1038/s41467-025-56378-9 |
| spellingShingle | 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 An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants Nature Communications |
| title | An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants |
| title_full | An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants |
| title_fullStr | An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants |
| title_full_unstemmed | An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants |
| title_short | An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants |
| title_sort | oligodendrocyte silencer element underlies the pathogenic impact of lamin b1 structural variants |
| url | https://doi.org/10.1038/s41467-025-56378-9 |
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