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

Miller, Clint L.; Anderson, Denise; Kundu, Ramendra K.; Raiesdana, Azad; Nürnberg, Sylvia; Diaz, Roxanne; Cheng, Karen; Leeper, Nicholas J.; Chen, Chung–Hsing; Chang, I–Shou; Schadt, Eric E.; Hsiung, Chao A.; Assimes, Themistocles L.; Quertermous, Thomas

doi:10.1371/journal.pgen.1003652

Cited by 65 publications

(91 citation statements)

References 57 publications

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“…TCF21 binds specific DNA sequences and negatively regulates various cell differentiation through modulating cell cycle arrest and tissue-specific gene expression (15), indicating that TCF21 has a role in the development of malignant tumors (16). Expression quantitative trait locus (eQTL) data and a reporter gene assay showed that the C allele of rs12190287 increased the expression of TCF21 in vascular smooth muscle cells (VSMCs) (2,17). An in vitro study of cultured MG63 cells showed that expression of the cyclin-dependent kinase inhibitor, P21, was reduced when TCF21 was introduced (15), indicating that TCF21 functions as a negative regulator of P21, which is crucial in VSMC proliferation (18).…”

Section: Discussionmentioning

confidence: 99%

Association of a transcription factor 21 gene polymorphism with hypertension

Fujimaki

Oguri²,

Horibe

et al. 2014

Biomedical Reports

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Abstract.Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ 2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P= 0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

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Section: Discussionmentioning

confidence: 99%

Association of a transcription factor 21 gene polymorphism with hypertension

Fujimaki

Oguri²,

Horibe

et al. 2014

Biomedical Reports

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“…The mesoderm-specific deletion of MOZ results in a high penetrance of VSDs and overriding aorta (Vanyai et al, 2015). Miller et al (2013) identified a cis-acting mechanism by which the TCF21 G allele at variant rs12190287 disrupts an atypical activator protein 1-like enhancer element to decrease the transcriptional control of TCF21 gene expression. Further study showed that the rs12190287 allele G results in a mismatch that disrupts miR-224 binding and accessibility of this region of the TCF21 3¢-UTR.…”

Section: Association Of Tcf21 Rs12190287 With Vsdmentioning

confidence: 99%

TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population

Yang

Gao²,

Luo³

et al. 2017

Genetic Testing and Molecular Biomarkers

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Aims: TCF21 knockout mice display cardiac defects, including ventricular septal defects (VSDs). Functional rs12190287 polymorphisms located within the 3¢ untranslated region (3¢-UTR) of TCF21 were associated with a risk of coronary heart disease in the European and Eastern populations. However, whether rs12190287 polymorphisms in the TCF21-3¢UTR confer predisposition to congenital heart disease (CHD) is unclear. Methods: A case-control study was designed consisting of 781 nonsyndromic VSD patients and 867 non-CHD control subjects. The genotype frequency of rs12190287 polymorphisms was determined by real-time polymerase chain reaction. Results: There were significant differences in the genotype and allele frequencies of rs12190287 between the cases and controls in a Chinese population. Allele G of rs12190287 was significantly associated with an increased risk of VSD in a Chinese population.Conclusions: Our results demonstrate that rs12190287 polymorphisms confer predisposition to VSDs in the Chinese population studied here.

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“…Given their similar patterns of expression in the developing epicardium, this result suggests therefore that Tcf21 and Lhx9 function coordinately to enable the correct clustering and migration of PE cells onto the heart surface through integrin-directed mechanisms. It is of interest to note that Tcf21 and LIM homeodomain transcription factors are both found to be essential for the development of the gonad and craniofacial structures (Moncaut et al, 2012;Harel et al, 2012;Cui et al, 2004;Birk et al, 2000), suggesting that the transcriptional targets of these two genes and the pathways they regulate might unveil a conserved mechanism of regulating cell motility and thus, would have implications in cancer, as well as cardiac and organ development (Vladimirova et al, 2009;Yang et al, 2015;Miller et al, 2014Miller et al, , 2013Weiss et al, 2013;Zhang et al, 2012;Ye et al, 2012;Richards et al, 2011;Arab et al, 2011).…”

Section: Lhx9 and Tcf21 During Epicardial Formationmentioning

confidence: 99%

The Lhx9-Integrin pathway is essential for positioning of the proepicardial organ

Tandon¹,

Wilczewski²,

Williams³

et al. 2016

Development

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The development of the vertebrate embryonic heart occurs by hyperplastic growth as well as the incorporation of cells from tissues outside of the initial heart field. Amongst these tissues is the epicardium, a cell structure that develops from the precursor proepicardial organ on the right side of the septum transversum caudal to the developing heart. During embryogenesis, cells of the proepicardial organ migrate, adhere and envelop the maturing heart, forming the epicardium. The cells of the epicardium then delaminate and incorporate into the heart giving rise to cardiac derivatives, including smooth muscle cells and cardiac fibroblasts. Here, we demonstrate that the LIM homeodomain protein Lhx9 is transiently expressed in Xenopus proepicardial cells and is essential for the position of the proepicardial organ on the septum transversum. Utilizing a small-molecule screen, we found that Lhx9 acts upstream of integrin-paxillin signaling and consistently demonstrate that either loss of Lhx9 or disruption of the integrin-paxillin pathway results in mis-positioning of the proepicardial organ and aberrant deposition of extracellular matrix proteins. This leads to a failure of proepicardial cell migration and adhesion to the heart, and eventual death of the embryo. Collectively, these studies establish a requirement for the Lhx9-integrin-paxillin pathway in proepicardial organ positioning and epicardial formation.

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

Cited by 65 publications

References 57 publications

Association of a transcription factor 21 gene polymorphism with hypertension

Association of a transcription factor 21 gene polymorphism with hypertension

TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population

The Lhx9-Integrin pathway is essential for positioning of the proepicardial organ

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