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

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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Publication Details

Journal
Nature Communications
Published
2025-10-03
DOI
https://doi.org/10.1038/s41467-025-63876-3
Primary Topic
Nuclear Structure and Function
Type
article
Field-Weighted Citation Impact
0.00
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article

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

Liao Tan, Wang Zh, Sudun Guan, Longjian Niu et al.
Nature Communications
Nuclear Structure and Function
article

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

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

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.

Nature CommunicationsVol. 16(1)
Central South University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Southern University of Science and Technology (CN), National Center for Nanoscience and Technology (CN), Xiangya Hospital Central South University (CN)
Openalex Percentile: Top 76%
Nuclear Structure and Function
DOIOpen Access PDFOpenAlex
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