Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer

Jae Ryeon Ryu, Suchit Ahuja, Corey R. Arnold, Kyle G. Potts, Aniket Mishra, Qiong Yang, Muralidharan Sargurupremraj, Douglas J. Mahoney, Sudha Seshadri, Stephanie Debette, Sarah J. Childs

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere2121333119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number35
DOIs
StatePublished - Aug 30 2022

Keywords

  • FOXF2
  • pericyte
  • stroke

ASJC Scopus subject areas

  • General

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