Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus

Clint L Miller,Ramendra K Kundu,Chao Agnes Hsiung,Chung-Hsing Chen,Themistocles L Assimes,Roxanne Diaz,D Ryan Anderson,Eric E Schadt,Azad Raiesdana,I-Shou Chang,Nicholas J Leeper,Sylvia T Nürnberg,Karen Cheng,Thomas Quertermous,Greg Gibson

doi:10.1371/journal.pgen.1003652

Abstract

Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.

Highlights

A recent meta-analysis of 14 Genome-wide association studies (GWAS) for Coronary heart disease (CHD), Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM), including 22,233 cases and 64,762 controls in Europeans, elucidated 13 novel susceptibility loci [1]
Loss of Tcf21 expression in mouse results in increased expression of SMC markers in cells on the heart surface consistent with premature SMC differentiation [7], and a dramatic failure of cardiac fibroblast development [6,7]. These data are most consistent with a role for Tcf21 in a bipotential precursor cell for SMC and cardiac fibroblast lineages, with loss of Tcf21 expression being essential for SMC development, and persistent Tcf21 expression being required for cardiac fibroblast development [6,7]
Genome-wide association studies in human populations have uncovered multiple sites of common genetic variation associated with heart disease

Summary

Introduction

A recent meta-analysis of 14 Genome-wide association studies (GWAS) for CHD, Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM), including 22,233 cases and 64,762 controls in Europeans, elucidated 13 novel susceptibility loci [1]. One of these novel loci includes a variant, rs12190287 at 6q23.2, located within the 39 untranslated region (39UTR) of TCF21 [1]. Loss of Tcf expression in mouse results in increased expression of SMC markers in cells on the heart surface consistent with premature SMC differentiation [7], and a dramatic failure of cardiac fibroblast development [6,7]. These data are most consistent with a role for Tcf in a bipotential precursor cell for SMC and cardiac fibroblast lineages, with loss of Tcf expression being essential for SMC development, and persistent Tcf expression being required for cardiac fibroblast development [6,7]

Methods

Results

Discussion

Conclusion