Abstract
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.
Highlights
We find that a well-known environmental sensor, aryl-hydrocarbon receptor (AHR), is regulated by TCF21 and interacts with TCF21, resulting in regulation of pro-inflammatory gene expression in coronary artery smooth muscle cells
Genome-wide association studies (GWAS) have identified susceptibility loci and candidate genetic variants that predispose to atherosclerotic coronary artery disease (CAD) in humans. [1,2,3,4] Despite significant advances made in mapping the genetic contribution to CAD, there has been limited progress toward understanding molecular mechanisms leading to increased atherosclerosis susceptibility that are mediated through gene-environment (GxE) interactions
aryl hydrocarbon receptor (AHR) is a TCF21 targeted gene differentially regulated in SMC
Summary
Genome-wide association studies (GWAS) have identified susceptibility loci and candidate genetic variants that predispose to atherosclerotic coronary artery disease (CAD) in humans. [1,2,3,4] Despite significant advances made in mapping the genetic contribution to CAD, there has been limited progress toward understanding molecular mechanisms leading to increased atherosclerosis susceptibility that are mediated through gene-environment (GxE) interactions. [5] The difficulty in identifying the role of genetic variation in the differential response to environmental exposure stems from inaccurate quantification of the exposure, the inability to isolate the exposures of interest, and the lack of statistical power.[6]GWA studies have identified variation at 6q23.2 to be associated with CAD in Caucasian and Han Chinese populations[1, 7], and work in this lab has identified TCF21 as the causal gene in this locus.[8, 9] Mechanistic studies employing lineage tracing in murine disease models have found that Tcf expression is localized to the medial and adventitial layers of the coronary vessel wall at baseline, and that Tcf expressing cells migrate through the lesion and contribute to the fibrous cap as disease progresses.[10]. Genome-wide association studies (GWAS) have identified susceptibility loci and candidate genetic variants that predispose to atherosclerotic coronary artery disease (CAD) in humans. [1,2,3,4] Despite significant advances made in mapping the genetic contribution to CAD, there has been limited progress toward understanding molecular mechanisms leading to increased atherosclerosis susceptibility that are mediated through gene-environment (GxE) interactions. [5] The difficulty in identifying the role of genetic variation in the differential response to environmental exposure stems from inaccurate quantification of the exposure, the inability to isolate the exposures of interest, and the lack of statistical power.[6]. We discovered one of the central components of the TCF21 gene network to be the aryl hydrocarbon receptor (AHR), a transcription factor that mediates the response to environmental toxins and xenobiotics, and is known to regulate the inflammatory cellular response.[13,14,15,16,17]
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