Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A.

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

Guangdong 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 University, Guangzhou, China. · pubmed

Paper

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.

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Research summary

The paper investigates the role of LMNA mutations in chromatin organization and their implications for stem cell aging, which directly relates to the mechanisms of aging and age-related diseases. While it provides solid insights into the chromatin alterations associated with a specific progeroid syndrome, the findings are somewhat niche and primarily focused on a specific patient case rather than broader applications or solutions to aging. Thus, while it contributes to the understanding of aging mechanisms, its overall impact on the field is limited.

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