TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

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.

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

“…[15][16][17][18] In disease, Tcf21 is reported to function as a tumor suppressor and loss of Tcf21 expression and/or methylation of its promoter have been identified in a variety of lung and urogenital tumors. 19,20 In other studies, Tcf21 has been linked to coronary artery disease, 21,22 podocyte differentiation, diabetic kidney disease, 23 and changes in adipose phenotype. 24 In the kidney, previous work has shown that Tcf21 null mutant mice are born with severely hypoplastic kidneys, and that although Tcf21 is exclusively expressed in the mesenchyme, in its absence, major defects in UB epithelial differentiation and branching are observed.…”

The environment-sensing aryl-hydrocarbon receptor inhibits the chondrogenic fate of modulated smooth muscle cells in atherosclerotic lesions

“…In our previous work, we have shown that TCF21, a highly replicated gene associated with CAD, interacts closely with AHR. 9 We also found that TCF21 plays a central role in regulating SMC phenotype and in modulating SMC phenotypic modulation during atherosclerosis. [10][11][12] However, the role of the AHR pathway in regulating SMC phenotypic modulation in atherosclerotic disease is not well understood.…”

LncRNA de novo discovery reveals noncoding RNAs as major molecular mechanism associating coronary artery disease GWAS variants with causal genes to confer disease risk

“…We have previously shown that TCF21 represents a potent factor in HCASMC that can shape the future of this cell type during embryogenesis and athero-development (Kim et al 2017;Nurnberg et al 2015;Sazonova et al 2015;Wirka et al 2019). One of the most important protective mechanisms during lesion formation and expansion is the phenotypic modulation of HCASMC.…”