The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity

  • Nat Commun. 2025 Oct 3;16(1):8826. doi: 10.1038/s41467-025-63876-3.
Wenqiang Li  #  1  2 ,  Yunxi Liao  #  2  3 ,  Zhujiang Liu  4 ,  Longjian Niu  5  6 ,  Jiaqi Huang  1  2 ,  Yiting Jia  2  7 ,  Ran Xu  8  9 ,  Sudun Guan  10 ,  Zhenhui Liang  1  2 ,  Yiran Li  1  2 ,  Hao Wu  1  2 ,  Shirong Zhu  1  2 ,  Liao Tan  11 ,  Fang Yu  1  2 ,  Zhihua Wang  12  13 ,  Luyang Sun  10 ,  Dongyu Zhao  14  15 ,  Wei Kong  16  17 ,  Yi Fu  18  19
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 3. Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 4. Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, China.
  • 5. School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, China.
  • 6. Shenzhen Key Laboratory of Cardiovascular Health and Precision Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 7. Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 8. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 9. China International Neuroscience Institute (China-INI), Beijing, China.
  • 10. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 11. Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Hunan, China.
  • 12. Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China.
  • 13. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 14. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 15. Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 16. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 17. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 18. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 19. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41044070 DOI: 10.1038/s41467-025-63876-3
Abstract

Maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) is critical for vascular homeostasis. However, the role of the 3D chromatin architecture in regulating VSMC identity remains elusive. A genome-scale CRISPR screen identifies LEMD3 as a potential regulator to maintain VSMC identity. Lemd3 deficiency in VSMCs results in the loss of the contractile phenotype and exacerbates intimal hyperplasia in mice. Protein interactome analysis reveals that LEMD3 interacts with CBX3, a principal reader of H3K9me2/3, subsequently anchoring heterochromatin at the nuclear periphery. Employing the DNA polymer model based on Hi-C data, whole-chromosome simulations demonstrate that Lemd3 depletion disturbs the chromatin structure. Multi-omics analysis further reveals that Lemd3 depletion alters the genome conformation as the increase of inter-TAD (topologically associated domain) interactions at the boundaries of A and B compartments, which correlates with decreased chromatin accessibility and repressed expression of VSMC contractile genes. This study reveals that LEMD3 organizes the 3D chromatin architecture by anchoring heterochromatin at the nuclear periphery to maintain the VSMC contractile identity.

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