Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A
Abstract Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Usi...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54338-3 |
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| author | Wei Jin Shaoshuai Jiang Xinyi Liu Yi He Tuo Li Jingchun Ma Zhihong Chen Xiaomei Lu Xinguang Liu Weinian Shou Guoxiang Jin Junjun Ding Zhongjun Zhou |
| author_facet | Wei Jin Shaoshuai Jiang Xinyi Liu Yi He Tuo Li Jingchun Ma Zhihong Chen Xiaomei Lu Xinguang Liu Weinian Shou Guoxiang Jin Junjun Ding Zhongjun Zhou |
| author_sort | Wei Jin |
| collection | DOAJ |
| description | Abstract Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome. |
| format | Article |
| id | doaj-art-4634a1454bc443bca2dcfc2e0909fc24 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4634a1454bc443bca2dcfc2e0909fc242025-08-20T02:33:31ZengNature PortfolioNature Communications2041-17232024-11-0115112110.1038/s41467-024-54338-3Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type AWei Jin0Shaoshuai Jiang1Xinyi Liu2Yi He3Tuo Li4Jingchun Ma5Zhihong Chen6Xiaomei Lu7Xinguang Liu8Weinian Shou9Guoxiang Jin10Junjun Ding11Zhongjun Zhou12Guangdong Cardiovascular Institute, Medical Research Institute, Guangdong Key Laboratory for Immune and Genetic Research of Chronic Nephropathy, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Key Laboratory for Stem Cells and Tissue Engineering of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen UniversityRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Key Laboratory for Stem Cells and Tissue Engineering of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen UniversitySchool of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong KongDepartment of Endocrinology, Changzheng HospitalSchool of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong KongSchool of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong KongDongguan Institute of Pediatrics, Dongguan Children’s HospitalGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Institute of Biochemistry & Molecular Biology, Guangdong Medical UniversityIndiana University School of MedicineGuangdong Cardiovascular Institute, Medical Research Institute, Guangdong Key Laboratory for Immune and Genetic Research of Chronic Nephropathy, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Key Laboratory for Stem Cells and Tissue Engineering of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen UniversityGuangdong Cardiovascular Institute, Medical Research Institute, Guangdong Key Laboratory for Immune and Genetic Research of Chronic Nephropathy, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityAbstract Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome.https://doi.org/10.1038/s41467-024-54338-3 |
| spellingShingle | Wei Jin Shaoshuai Jiang Xinyi Liu Yi He Tuo Li Jingchun Ma Zhihong Chen Xiaomei Lu Xinguang Liu Weinian Shou Guoxiang Jin Junjun Ding Zhongjun Zhou Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A Nature Communications |
| title | Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A |
| title_full | Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A |
| title_fullStr | Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A |
| title_full_unstemmed | Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A |
| title_short | Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A |
| title_sort | disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy based progeria mandibuloacral dysplasia type a |
| url | https://doi.org/10.1038/s41467-024-54338-3 |
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