What question did this study set out to answer?

To explore how the SNP rs11574 in the ID3 gene alters its function and affects cellular processes.

January 18, 2026Open Access

A prevalent disease-associated SNP in the human ID3 gene regulates E-protein activity and cellular proliferation

Puntos clave

To explore how the SNP rs11574 in the ID3 gene alters its function and affects cellular processes.
Examined the effects of the rs11574 SNP on ID3 and E12 binding through computational analysis and biochemical experiments.
Utilized isogenic human cell lines carrying the rs11574 allele to assess changes in cell proliferation and gene expression.
Conducted RNA sequencing to investigate the roles of E12 and E47 in vascular smooth muscle cells.
The minor allele of rs11574 disrupts ID3’s binding with the E-protein E12.
Cells with the minor allele show reduced cell proliferation and changes in gene expression linked to proliferation.
Distinct transcriptional roles identified for E12 and E47 in vascular smooth muscle cells.

Resumen

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.

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