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A Prevalent Disease-Associated SNP in the Human ID3 Gene Regulates E-Protein Activity and Cellular Proliferation [VMSC RNA-Seq]

ABSTRACT: The helix-loop-helix transcription factor ID3 is a critical regulator of tissue development and homeostasis. Aberrations in ID3 are strongly associated with numerous human disease processes including Burkitt’s lymphoma. We previously identified that a single nucleotide polymorphism (SNP) in ID3 at rs11574 is associated with increased vascular disease burden in three independent cohorts; however, the mechanisms by which this SNP alters ID3 function and impacts vascular cells are unknown. Here, we show that the minor allele of rs11574 specifically disrupts ID3’s ability to bind the E-protein E12. Computational analysis and confirmatory biochemical experiments revealed that rs11574’s effects on ID3:E12 dimerization are dependent upon a key residue within E12’s unique loop domain. Functionally, the disruption of ID3:E12 binding promotes E12 binding to and activation of the p21 promoter. Isogenic human cell lines harboring the rs11574 minor allele exhibited decreased cell proliferation and altered expression of genes involved in proliferation. RNAseq revealed distinct roles for E12 and E47 in transcriptional regulation of vascular smooth muscle cells (VSMCs). Primary human VSMCs from subjects with the rs11574 minor allele exhibited reduced mitogen-stimulated proliferation. Taken together, these results provide the first characterization of altered molecular and cellular functions of this disease-associated SNP in ID3 at rs11574.

ORGANISM(S): Mus musculus

PROVIDER: GSE316072 | GEO | 2026/01/09

REPOSITORIES: GEO

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Project description:Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown.Here we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury to understand the cellular mechanisms underlying clonal VSMC expansion in disease.We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. We show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.

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A Prevalent Disease-Associated SNP in the Human ID3 Gene Regulates E-Protein Activity and Cellular Proliferation [VMSC RNA-Seq]

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