284: FES, VSMC behavior and pleiotropic vascular genes identified by integrative functional genomics

Solomon CU et al., Nat Commun(2026). - Integrative analysis in human VSMCs identifies pleiotropic genes including FES that regulate vascular remodeling; pooled CRISPR and mouse knockout show FES loss increases MMPs, atherosclerosis and blood pressure. Key terms: FES, vascular smooth muscle cell, atherosclerosis, colocalization eQTL, CRISPR knockout screen.

Study Highlights:
The study used a large human umbilical cord‑derived VSMC eQTL bank (n=1,486) combined with colocalization (eCAVIAR, SMR/HEIDI), ATAC‑seq, DNA methylation, H3K27ac HiChIP and pooled CRISPR‑Cas9 knockout screens to nominate likely causal genes for CAD, hypertension, stroke and AAA. Pooled CRISPR screens and siRNA validation in VSMCs highlighted BCAR1, CARF, SMARCA4 and FES as modulators of VSMC proliferation or migration, while FES knockdown increased MMP1/MMP3, reduced contractile markers and promoted migration by RNA‑seq and proteomics/phosphoproteomics. In vivo, Fes‑/-/Apoe‑/- mice had larger en face aortic lesion areas (8.34±2.54% vs 6.06±2.35%, P=0.013) and higher baseline systolic/diastolic blood pressure (104.4±6.7 vs 88.0±10.1 mmHg and 74.9±9.0 vs 58.8±8.9 mmHg, P=0.042). These results support FES as a pleiotropic, potentially druggable regulator of VSMC phenotype with functional effects on atherosclerosis and blood pressure.

Conclusion:
Integrative functional genomics implicates panels of likely causal and pleiotropic genes, including FES, that regulate VSMC behavior and whose loss promotes VSMC dedifferentiation, increased MMP production, larger atherosclerotic lesions and higher blood pressure.

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Article title:
Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases

First author:
Solomon CU

Journal:
Nat Commun(2026).

DOI:
10.1038/s41467-026-69273-8

Reference:
Solomon CU, McVey DG, Andreadi C, Peng G, Turner L, Song DSS, Zhang H, Lee DP, Karamanavi E, Yang W, Chu J, Chen R, Haworth KE, Anene-Nzelu CG, Li H, Denniff MJ, Li PY, Zhang Y, Huang X, Morris GE, Greer PA, Stringer EJ, Yu H, Foo RSY, Douglas G, Samani NJ, Webb TR, Ye S. Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69273-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-08.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive portions of the transcript describing FES as a pleiotropic regulator of vascular disease, VSMC phenotypic switching, CRISPR knockouts, mouse model results, UK Biobank human genetics, and therapeutic implications.
- transcript topics: Pleiotropy across vascular diseases; FES as a master regulator in vascular smooth muscle cells (VSMCs); VSMC phenotypic switching, migration, and MMP production; Pooled CRISPR-Cas9 knockout screens and validation; Mouse model: Fes knockout and atherosclerosis/blood pressure; UK Biobank human genetics for FES variants

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged...