Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer
- Ryu, J.R., Ahuja, S., Arnold, C.R., Potts, K.G., Mishra, A., Yang, Q., Sargurupremraj, M., Mahoney, D.J., Seshadri, S., Debette, S., Childs, S.J.
- Proceedings of the National Academy of Sciences of the United States of America 119: e2121333119 (Journal)
- Registered Authors
- Childs, Sarah J.
- FOXF2, pericyte, stroke
- MeSH Terms
- DNA, Intergenic/genetics
- DNA, Intergenic/metabolism
- Forkhead Transcription Factors*/genetics
- Forkhead Transcription Factors*/metabolism
- Genomic Structural Variation/genetics
- Polymorphism, Single Nucleotide
- Transcriptional Activation/genetics
- 35994645 Full text @ Proc. Natl. Acad. Sci. USA
Ryu, J.R., Ahuja, S., Arnold, C.R., Potts, K.G., Mishra, A., Yang, Q., Sargurupremraj, M., Mahoney, D.J., Seshadri, S., Debette, S., Childs, S.J. (2022) Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer. Proceedings of the National Academy of Sciences of the United States of America. 119:e2121333119.
SNPs associated with human stroke risk have been identified in the intergenic region between Forkhead family transcription factors FOXF2 and FOXQ1, but we lack a mechanism for the association. FoxF2 is expressed in vascular mural pericytes and is important for maintaining pericyte number and stabilizing small vessels in zebrafish. The stroke-associated SNPs are located in a previously unknown transcriptional enhancer for FOXF2, functional in human cells and zebrafish. We identify critical enhancer regions for FOXF2 gene expression, including binding sites occupied by transcription factors ETS1, RBPJ, and CTCF. rs74564934, a stroke-associated SNP adjacent to the ETS1 binding site, decreases enhancer function, as does mutation of RPBJ sites. rs74564934 is significantly associated with the increased risk of any stroke, ischemic stroke, small vessel stroke, and elevated white matter hyperintensity burden in humans. Foxf2 has a conserved function cross-species and is expressed in vascular mural pericytes of the vessel wall. Thus, stroke-associated SNPs modulate enhancer activity and expression of a regulator of vascular stabilization, FOXF2, thereby modulating stroke risk.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes