biostudies-literatureLi WNational Natural Science Foundation of China (National Science Foundation of China)8826https://www.ebi.ac.uk/biostudies/studies/S-EPMC12495022biostudies-literatureUnknown16(1)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 depletiNature communicationsThe inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity.PMC1249502282100436918393028240049681921001915392033193005681900261Tan LLiao YHuang JXu RLiang ZGuan SYu FFu YWu HLi WSun LLiu ZLi YJia YNiu LZhao DWang ZZhu SKong WfalseThe 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 depleti2025-01-01T00:00:00Z2025 Oct2026-07-15T05:47:20.166Z2026-06-29T03:19:46.951ZS-EPMC124950224104407010.1038/s41467-025-63876-3