| 11080479 | TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney. | Gooskens SL, etal., Oncotarget. 2015 Jun 30;6(18):15828-41. | Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmenta l chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10;17)(q22;p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10;17)(q22;p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK. | 26158413 | 2015-05-01 |
| 11061321 | Clinicopathological significance and biological role of TCF21 mRNA in breast cancer. | Wang J, etal., Tumour Biol. 2015 Nov;36(11):8679-83. doi: 10.1007/s13277-015-3476-1. Epub 2015 Jun 6. | TCF21 is known to function as a tumor suppressor and deregulated in several types of cancers; however, its role in breast cancer remains poorly understood. The aim of this study was to examine the expression of TCF21 messeng er RNA (mRNA) in breast cancer and evaluate its clinical significance and biological role in tumor progression. TCF21 mRNA expression was analyzed in breast cancer cell lines and tissues by qRT-PCR. Overexpression approach was used to investigate the biological functions of TCF21 mRNA in breast cancer cell line (MDA-MB-231). A notably lower level of TCF21 mRNA expression was found in breast cancer cell lines and tissues. Furthermore, the low expression of TCF21 mRNA was associated with large tumor size and positive lymph node metastasis. Functional analysis showed that overexpression of TCF21 mRNA inhibited cell proliferation and epithelial-mesenchymal transition (EMT) of MDA-MB-231. In conclusion, our data provided the first evidence that TCF21 mRNA is significantly downregulated in breast cancer cell lines and tissues and regulates breast cancer cell proliferation and EMT. Thus, TCF21 may act as a potential therapeutic target for breast cancer intervention. | 26044559 | 2015-04-01 |
| 329337356 | Association Between TCF21 Gene Polymorphism with the Incidence of Paroxysmal Atrial Fibrillation and the Efficacy of Radiofrequency Ablation for Patients with Paroxysmal Atrial Fibrillation. | Zhang X, etal., Int J Gen Med. 2022 May 16;15:4975-4983. doi: 10.2147/IJGM.S366956. eCollection 2022. |
PURPOSE: Atrial fibrillation (AF) is the most common sustained arrhythmia with a high rate of recurrence after catheter ablation. The gene encoding transcription factor 21 (TCF21) has been linked to coronary artery disease risk by human genome-wide association studies in multiple racial ethnic groups. However, the association of TCF21 with AF remains unclear.
PATIENTS AND METHODS: Circulating leukocytes in patients with paroxysmal AF (PAF) and 92 age-matched controls without a history of cardiovascular disease, AF and other arrhythmias were collected. A total of 224 PAF patients receiving radiofrequency ablation had an 18-month scheduled follow-up study for recurrence of AF. Three single-nucleotide polymorphisms (SNPs) of TCF21 (rs2327429, rs2327433 and rs12190287) were genotyped by PCR, and serum levels of TCF21 were measured by ELISA.
RESULTS: More males and smokers were observed in the PAF group compared with controls. C allele of rs2327429, G allele and GG genotype of rs12190287 were markedly associated with the increased onset of PAF. The levels of serum TCF21 were significantly higher in PAF group than those in control group (1.96 ± 0.85 vs 0.86 ± 0.49 ng/mL, P<0.001). Based on logistic regression analysis, we confirmed that risk allele at rs12190287 and serum TCF21 concentration were independently correlated with the incidence of PAF. Furthermore, GG genotype of rs12190287 enhanced the susceptibility of AF recurrence after ablation.
CONCLUSION: G allele and GG genotype of rs12190287 in TCF21 and elevated TCF21 concentration are significantly associated with the onset of PAF and recurrence after ablation. | 35601004 | 2022-12-01 |
| 8553815 | Basic helix-loop-helix transcription factor TCF21 is a downstream target of the male sex determining gene SRY. | Bhandari RK, etal., PLoS One. 2011;6(5):e19935. doi: 10.1371/journal.pone.0019935. Epub 2011 May 17. | The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex determining factor SRY as the b asic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to bind to the Tcf21 promoter and activate gene expression. Mutagenesis of SRY/SOX9 response elements in the Tcf21 promoter eliminated the actions of SRY. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation. TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes. Therefore, SRY acts directly on the Tcf21 promoter to in part initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development. | 21637323 | 1000-05-01 |
| 11057596 | Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci. | Sazonova O, etal., PLoS Genet. 2015 May 28;11(5):e1005202. doi: 10.1371/journal.pgen.1005202. eCollection 2015 May. | To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription fa ctor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology. | 26020271 | 2015-04-01 |
| 329347821 | Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk. | Iyer D, etal., PLoS Genet. 2018 Oct 11;14(10):e1007681. doi: 10.1371/journal.pgen.1007681. eCollection 2018 Oct. | Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk. | 30307970 | 2018-10-01 |
| 329337355 | Coronary Disease-Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway. | Nagao M, etal., Circ Res. 2020 Feb 14;126(4):517-529. doi: 10.1161/CIRCRESAHA.119.315968. Epub 2019 Dec 9. |
RATIONALE: The gene encoding TCF21 (transcription factor 21) has been linked to coronary artery disease risk by human genome-wide association studies in multiple racial ethnic groups. In murine models, Tcf21 is required for phenotypic modulation of smooth muscle cells (SMCs) in atherosclerotic tissues and promotes a fibroblast phenotype in these cells. In humans, TCF21 expression inhibits risk for coronary artery disease. The molecular mechanism by which TCF21 regulates SMC phenotype is not known.
OBJECTIVE: To better understand how TCF21 affects the SMC phenotype, we sought to investigate the possible mechanisms by which it regulates the lineage determining MYOCD (myocardin)-SRF (serum response factor) pathway.
METHODS AND RESULTS: Modulation of TCF21 expression in human coronary artery SMC revealed that TCF21 suppresses a broad range of SMC markers, as well as key SMC transcription factors MYOCD and SRF, at the RNA and protein level. We conducted chromatin immunoprecipitation-sequencing to map SRF-binding sites in human coronary artery SMC, showing that binding is colocalized in the genome with TCF21, including at a novel enhancer in the SRF gene, and at the MYOCD gene promoter. In vitro genome editing indicated that the SRF enhancer CArG box regulates transcription of the SRF gene, and mutation of this conserved motif in the orthologous mouse SRF enhancer revealed decreased SRF expression in aorta and heart tissues. Direct TCF21 binding and transcriptional inhibition at colocalized sites were established by reporter gene transfection assays. Chromatin immunoprecipitation and protein coimmunoprecipitation studies provided evidence that TCF21 blocks MYOCD and SRF association by direct TCF21-MYOCD interaction.
CONCLUSIONS: These data indicate that TCF21 antagonizes the MYOCD-SRF pathway through multiple mechanisms, further establishing a role for this coronary artery disease-associated gene in fundamental SMC processes and indicating the importance of smooth muscle response to vascular stress and phenotypic modulation of this cell type in coronary artery disease risk. | 31815603 | 2020-02-14 |
| 329337360 | Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation. | Miller CL, etal., PLoS Genet. 2014 Mar 27;10(3):e1004263. doi: 10.1371/journal.pgen.1004263. eCollection 2014 Mar. | Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this r egion, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants. | 24676100 | 2014-03-01 |
| 329337359 | CXCL12 promotes atherosclerosis by downregulating ABCA1 expression via the CXCR4/GSK3β/β-cateninT120/TCF21 pathway. | Gao JH, etal., J Lipid Res. 2019 Dec;60(12):2020-2033. doi: 10.1194/jlr.RA119000100. Epub 2019 Oct 29. | CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid met abolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding to its promoter region, which was repressed by CXCL12. We found that CXCL12 increased the levels of phosphorylated glycogen synthase kinase 3β (GSK3β) and the phosphorylation of β-catenin at the Thr120 position. Inactivation of GSK3β or β-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on TCF21 and ABCA1 expression and the phosphorylation of GSK3β and β-catenin. In vivo, the overexpression of CXCL12 in Apoe-/- mice via lentivirus enlarged the atherosclerotic lesion area and increased macrophage infiltration in atherosclerotic plaques. We further found that the overexpression of CXCL12 reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), and suppressed cholesterol efflux from MPMs to apoA-I in Apoe-/- mice. Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then activates the GSK-3β/β-cateninT120/TCF21 signaling pathway to inhibit ABCA1-dependent cholesterol efflux from macrophages and aggravate atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the prevention and treatment of atherosclerotic cardiovascular diseases. | 31662443 | 2019-12-01 |
| 11086066 | Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer. | Dai Y, etal., Biochem Biophys Res Commun. 2016 Jan 15;469(3):430-6. doi: 10.1016/j.bbrc.2015.09.109. Epub 2015 Dec 17. | Epigenetic alteration induced loss function of the transcription factor 21 (TCF21) has been associated with different types of human cancers. However, the epigenetic regulation and molecular functions of TCF21 in colorectal cancer (CRC) remain unknown. In this study, TCF21 expression levels and methylation status of its promoter region in CRC cell lines (n = 5) and CRC tissues (n = 151) as well as normal colorectal mucosa (n = 30) were assessed by RTq-PCR and methylation analysis (methylation specific PCR, MSP and bisulfite sequencing PCR, BSP), respectively. The cellular functions of TCF21 on CRC cell proliferation, apoptosis, invasion and migration were investigated in vitro. Our data revealed that TCF21 was frequently silenced by promoter hypermethylation in both tested CRC cell lines and primary CRC, and correlation analysis between methylation status and clinicopathologic parameters found that TCF21 methylation was significantly correlated with lymph node invasion (P = 0.013), while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of TCF21 in CRC cell lines, and cellular function experiments revealed that restoration of TCF21 inhibited CRC cell proliferation, promoted apoptosis and suppressed cell invasion and migration, suggesting that TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development. | 26435499 | 2016-06-01 |
| 329337364 | MiRNA-Related Polymorphisms in miR-146a and TCF21 Are Associated with Increased Susceptibility to Coronary Artery Disease in an Iranian Population. | Bastami M, etal., Genet Test Mol Biomarkers. 2016 May;20(5):241-8. doi: 10.1089/gtmb.2015.0253. Epub 2016 Feb 24. |
AIMS: Recent studies have suggested that single-nucleotide polymorphisms (SNPs) in miRNA genes or their binding sites may alter an individual's susceptibility to coronary artery disease (CAD). In the present study, the association between two such SNPs (rs2910164 in miR-146a and rs12190287, which disrupts miRNA binding to TCF21) and CAD, in an Iranian population, was evaluated and in silico analyses were conducted to predict disease-related effects of miR-146a rs2910164.
METHODS: The study population consisted of angiographically confirmed CAD patients (n = 300) and asymptomatic controls (n = 300). Genotyping was performed using the TaqMan genotyping assay.
RESULTS: A multivariate regression analysis revealed that rs2910164 was associated with an increased CAD risk in the dominant model. In comparison to GG homozygotes, individuals who carry at least one C allele had a significantly higher risk of CAD (GC+CC vs. GG, odds ratios [OR]: 1.82, 95% confidence intervals [CI]: 1.18-2.80, p = 6.358e-3). Similarly, TCF21 rs12190287 was observed to be associated with CAD in a log-additive model (OR: 0.63, 95% CI: 0.45-0.88, p = 6.584e-3). An in silico analysis revealed that rs2910164 may modify the miR-146a-3p-mediated regulation of several biological processes that are implicated in CAD, like those that are related to the regulation of apoptosis and immune response.
CONCLUSIONS: Our data provide the first evidence for the association of miR-146a rs2910164 and TCF21 rs12190287 with CAD in an Iranian population, encouraging further research to elucidate the disease-related effects of miR-146a rs2910164. | 26909569 | 2016-05-01 |
| 11353463 | POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells. | Franca MM, etal., Biomed Res Int. 2015;2015:841784. doi: 10.1155/2015/841784. Epub 2015 Sep 2. | POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers. | 26421305 | 1000-07-01 |
| 11085664 | Regional differences in WT-1 and Tcf21 expression during ventricular development: implications for myocardial compaction. | Vicente-Steijn R, etal., PLoS One. 2015 Sep 21;10(9):e0136025. doi: 10.1371/journal.pone.0136025. eCollection 2015. | BACKGROUND: Morphological and functional differences of the right and left ventricle are apparent in the adult human heart. A differential contribution of cardiac fibroblasts and smooth muscle cells (populations of epicardium-derived cells) to each ventricle may account for part of the morphological -functional disparity. Here we studied the relation between epicardial derivatives and the development of compact ventricular myocardium. RESULTS: Wildtype and Wt1CreERT2/+ reporter mice were used to study WT-1 expressing cells, and Tcf21lacZ/+ reporter mice and PDGFRalpha-/-;Tcf21LacZ/+ mice to study the formation of the cardiac fibroblast population. After covering the heart, intramyocardial WT-1+ cells were first observed at the inner curvature, the right ventricular postero-lateral wall and left ventricular apical wall. Later, WT-1+ cells were present in the walls of both ventricles, but significantly more pronounced in the left ventricle. Tcf21-LacZ + cells followed the same distribution pattern as WT-1+ cells but at later stages, indicating a timing difference between these cell populations. Within the right ventricle, WT-1+ and Tcf21-lacZ+ cell distribution was more pronounced in the posterior inlet part. A gradual increase in myocardial wall thickness was observed early in the left ventricle and at later stages in the right ventricle. PDGFRalpha-/-;Tcf21LacZ/+ mice showed deficient epicardium, diminished number of Tcf21-LacZ + cells and reduced ventricular compaction. CONCLUSIONS: During normal heart development, spatio-temporal differences in contribution of WT-1 and Tcf21-LacZ + cells to right versus left ventricular myocardium occur parallel to myocardial thickening. These findings may relate to lateralized differences in ventricular (patho)morphology in humans. | 26390289 | 1000-06-01 |
| 329337362 | TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population. | Yang L, etal., Genet Test Mol Biomarkers. 2017 May;21(5):312-315. doi: 10.1089/gtmb.2016.0324. Epub 2017 Mar 27. |
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. | 28346832 | 2017-05-01 |
