Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A
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.
Authors
- Shaoshuai Jiang
- Xinguang Liu (ORCID: https://orcid.org/0000-0001-9033-9099)
- Weinian Shou (ORCID: https://orcid.org/0000-0001-5538-9605)
- Zhongjun Zhou (ORCID: https://orcid.org/0000-0001-7092-8128)
- Guoxiang Jin (ORCID: https://orcid.org/0000-0001-8989-0393)
- Junjun Ding (ORCID: https://orcid.org/0000-0002-9936-882X)
- Xinyi Liu (ORCID: https://orcid.org/0000-0003-0241-5499)
- Zhihong Chen (ORCID: https://orcid.org/0000-0002-7359-9056)
- Wei Jin (ORCID: https://orcid.org/0000-0002-6721-3460)
- Tuo Li (ORCID: https://orcid.org/0000-0002-6691-7423)
- Xiaomei Lu (ORCID: https://orcid.org/0000-0001-5454-1548)
- Yi He (ORCID: https://orcid.org/0000-0003-3939-0168)
- Jingchun Ma
Institutions
- Sun Yat-sen University (CN)
- Guangdong Medical College (CN)
- Chinese University of Hong Kong (HK)
- Sun Yat-sen Memorial Hospital (CN)
- Shanghai Changzheng Hospital (CN)
- Dongguan People’s Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Southern Medical University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41467-024-54338-3
- Citations
- 5
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Guangdong Innovative and Entrepreneurial Research Team Program
- National Natural Science Foundation of China
- Guangdong Provincial People's Hospital
- Basic and Applied Basic Research Foundation of Guangdong Province