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Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer
Jae-Ryeon Ryu1,2, Suchit Ahuja1,2, Corey R Arnold1,2
1Alberta Children's Hospital Research Institute, University of Calgary, Calgary AB T2N 4N1, Canada.
Summary
Genetic variations near the FOXF2 gene impact stroke risk by altering a key enhancer region. This finding reveals a mechanism linking vascular stabilization to stroke susceptibility.
Area of Science:
- Genetics
- Vascular Biology
- Neuroscience
Background:
- Single Nucleotide Polymorphisms (SNPs) linked to stroke risk are found between FOXF2 and FOXQ1 genes.
- The precise mechanism connecting these SNPs to stroke risk remains unclear.
- FOXF2 is crucial for vascular stability, particularly in pericytes.
Purpose of the Study:
- To elucidate the functional mechanism underlying stroke-associated SNPs.
- To identify the transcriptional regulatory elements controlling FOXF2 expression.
- To investigate the role of FOXF2 in vascular integrity and stroke pathogenesis.
Main Methods:
- Identification and functional characterization of a novel transcriptional enhancer for FOXF2.
- Analysis of transcription factor binding sites (ETS1, RBPJ, CTCF) within the enhancer region.
- Genomic analysis of stroke-associated SNPs, including rs74564934, in human populations.
Main Results:
- Stroke-associated SNPs are located within a functional enhancer of the FOXF2 gene.
- The SNP rs74564934, near an ETS1 binding site, reduces enhancer activity.
- Disruption of RBPJ binding sites also impairs enhancer function.
- rs74564934 is significantly associated with increased risk for various stroke types and white matter hyperintensities.
Conclusions:
- Stroke-associated SNPs modulate FOXF2 enhancer activity, impacting gene expression.
- FOXF2, a regulator of vascular stabilization, plays a conserved role across species.
- This study provides a mechanistic link between genetic risk factors and vascular dysfunction in stroke.
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