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

Author

Listed:
  • Wei Jin

    (Southern Medical University
    Chinese Academy of Sciences
    The University of Hong Kong)

  • Shaoshuai Jiang

    (Sun Yat-Sen University)

  • Xinyi Liu

    (Sun Yat-Sen University)

  • Yi He

    (The University of Hong Kong)

  • Tuo Li

    (Changzheng Hospital)

  • Jingchun Ma

    (The University of Hong Kong)

  • Zhihong Chen

    (The University of Hong Kong
    Sun Yat‐Sen University)

  • Xiaomei Lu

    (Dongguan Children’s Hospital)

  • Xinguang Liu

    (Guangdong Medical University)

  • Weinian Shou

    (Indiana University School of Medicine)

  • Guoxiang Jin

    (Southern Medical University)

  • Junjun Ding

    (Sun Yat-Sen University)

  • Zhongjun Zhou

    (Southern Medical University
    The University of Hong Kong
    University of Hong Kong-Shenzhen Hospital)

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.

Suggested Citation

  • 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, 2024. "Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54338-3
    DOI: 10.1038/s41467-024-54338-3
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