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<p>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. <i>Lemd3</i> 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 <i>Lemd3</i> depletion disturbs the chromatin structure. Multi-omics analysis further reveals that <i>Lemd3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Wenqiang Li,
  • Yunxi Liao,
  • Zhujiang Liu,
  • Longjian Niu,
  • Jiaqi Huang,
  • Yiting Jia,
  • Ran Xu,
  • Sudun Guan,
  • Zhenhui Liang,
  • Yiran Li,
  • Hao Wu,
  • Shirong Zhu,
  • Liao Tan,
  • Fang Yu,
  • Zhihua Wang,
  • Luyang Sun,
  • Dongyu Zhao,
  • Wei Kong,
  • Yi Fu

摘要

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.