Abstract 18374: TCF21 and Aryl-Hydrocarbon Receptor Gene Cooperate to Activate a Pro-Atherosclerotic Gene Expression Program
Background: Recently, the TCF21 gene was linked to the highly replicated coronary artery disease (CAD) associated polymorphism in the 6q23 locus. We previously reported Aryl Hydrocarbon Receptor (AHR) to be a downstream target of TCF21. AHR is a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g. cigarette), and has recently been associated with CAD in mice and humans. We further characterized the interaction between TCF21 and AHR.
Methods: The co-regulatory role of TCF21 and AHR on transcription was tested using dual luciferase assay. Luciferase reporter vector containing TCF21 and AHR binding motifs were transfected into HEK293 cells, with or without TCF21 expressing plasmid. These cells were then treated with 2,3,7,8-Tetrachlorodibenxo-p-dioxin (TCDD) or control. Laser capture microdissection (LCM) was performed on atherosclerotic plaque of Apoe (-/-) mouse on high fat diet for 12 weeks. Previously performed ChIP-Seq and ATAC-Seq (Assay for Transposase-Accessible Chromatin using sequencing) data from human coronary artery smooth muscle cells (HCASMC) were analyzed. Position weight matrix for TCF21 and AHR were obtained from the JASPAR database.
Results: We found that TCF21 over-expression and AHR pathway activation additively increased downstream transcription using reporter assay. Furthermore, we found AHR level to be higher in plaque in human and mouse atherosclerotic plaques. The TCF21 and AHR binding sites co-localized genome-wide to open chromatin regions of HCASMC, and genes near the overlapped binding sites enriched for pathways relevant to atherosclerosis, including cytokine production, migration and ossification. Using published ChIP-Seq data, we also found that common peaks of AHR-ARNT and TCF21 ChIP-Seq enriched for GWAS SNPs related to coronary artery disease.
Conclusion: The binding sites of two TFs, TCF21 and AHR, co-localize in HCASMC, and cooperate in transcriptional activation of downstream genes relevant to atherosclerosis. The functional link between TCF21 and AHR provides an opportunity to explore gene by environment interactions in the pathogenesis of CAD.
Author Disclosures: J.B. Kim: None. M. Pjanic: None. O. Sazanova: None. T. Wang: None. T. Nguyen: None. C. Miller: None. L. Maegdefessel: None. U. Hedin: None. T. Quertermous: None.
- © 2016 by American Heart Association, Inc.