Liganded retinoic acid X receptor α represses connexin 43 through a potential retinoic acid response element in the promoter region

Gu, Rong; Xu, Jun; Lin, Yi‐Dan; Zhang, Jing; Wang, Huijun; Sheng, Wei; Ma, Duan; Ma, Xiaojing; Huang, Guoying

doi:10.1038/pr.2016.47

Cited by 6 publications

(11 citation statements)

References 41 publications

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“…And the single nucleotide polymorphism rs2071166 located within a functional retinoic acid response element (Fig 1, repeating element with black background). 17,18 We identified two alleles (A and C) and three genotypes (AA, AC, and CC) at rs2071166 in both groups (Fig 2, Table 3). The frequency of Cx43 rs2071166 genotypes were 62.7% (AA), 21.3% (AC), 16% (CC) in patients with atrial septal defects and 67.0% (AA), 28.3% (AC), 4.7% (CC) in healthy controls ( Table 3).…”

Section: Resultsmentioning

confidence: 83%

“…18 The retinoic acid response element was critical in retinoic acid regulating Cx43 transcription activity and expression level. 18 Thus, we speculated that this single nucleotide polymorphism might change the efficiency of Cx43 transcription through damaging the function of the retinoic acid response element in Cx43. To further investigate our hypothesis, more molecular biology experiments such as luciferase transfection assay, electrophoretic mobility shift assay (EMSA), and transgenic knock-in animal models should be carried out to figure out the mechanism in CC genotype at rs2071166 affecting the retinoic acid response element in Cx43 and analyse the phenotype of the embryo heart.…”

Section: Discussionmentioning

confidence: 99%

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Association ofCx43rs2071166 polymorphism with an increased risk for atrial septal defect

Wei

et al. 2017

Cardiol Young

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Atrial septal defect is one of the most common CHD. The pathogenesis of atrial septal defect still remains unknown. Cx43 is the most prevalent connexin in the mammalian heart during development. Its genetic variants can cause several CHD. The aim of our study was to investigate the association of genetic variations of the Cx43 with sporadic atrial septal defect. A total of 450 paediatric patients were recruited, including 150 cases with atrial septal defect and 300 healthy controls. The promoter region of Cx43 was analysed by sequencing after polymerase chain reaction. All data were analysed by using the Statistic Package for Social Science 19.0 software. The frequency of the single nucleotide polymorphism rs2071166 was significantly higher in atrial septal defect cases than in healthy controls. The CC genotype at rs2071166 site in Cx43 was correlated with an increased risk for atrial septal defect (p<0.0001, odds ratio=3.891, 95% confidence interval 1.948-7.772) and the C allele was positively correlated with atrial septal defect (p=0.007, odds ratio=1.567, 95% confidence interval 1.129-2.175). In conclusion, our results confirmed that rs2071166 in Cx43 may be relevant with an increased atrial septal defect risk.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Association ofCx43rs2071166 polymorphism with an increased risk for atrial septal defect

Wei

et al. 2017

Cardiol Young

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“…The RARE also lost its regulatory function with the C variant. In our previous study, we found that RXRα can bind directly to the RARE 23 . Our EMSA data show that the C allele can alter the interaction between transcription factors and the sequence element.…”

Section: Discussionmentioning

confidence: 93%

“…observed that rs371954924 in WNT5A reduced gene expression by attenuating the binding affinity of the transcription factor SOX9 43 . In our previous study, we identified a functional RARE in the Cx43 promoter 23 . A genetic variant in the Cx43 promoter was located within the functional RARE.…”

Section: Discussionmentioning

confidence: 99%

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The role of histone modification and a regulatory single-nucleotide polymorphism (rs2071166) in the Cx43 promoter in patients with TOF

Lin

et al. 2017

Sci Rep

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Abnormal level of Cx43 expression could result in CHD. Epigenetic modification and disease-associated, non-coding SNPs might influence gene transcription and expression. Our study aimed to determine the role of histone modification and an rSNP (rs2071166) in the Cx43 promoter in patients with TOF. Our results indicate that H3K18ac bind to Cx43 promoter and that their levels are reduced in TOF patients relative to controls. The relationship between the non-coding SNP in the Cx43 gene and TOF patients was evaluated in 158 patients and 300 controls. The C allele of rs2071166 was confirmed to result in an increased risk of TOF (OR = 1.586, 95%CI 1.149–2.189). Individuals with the CC genotype at rs2071166 also showed a significant susceptibility to TOF (OR = 2.961, 95%CI 1.452–6.038). The mRNA level in TOF who were CC genotype was lower than that in patients with the AA/AC genotype. Functional analysis in cells and transgenic zebrafish models showed that rs2071166 decreased the activity of the promoter and could block the interaction between RXRα and RARE. This is the first study to illustrate that epigenetic modification and an rSNP in the Cx43 promoter region play a critical role in TOF by impacting the transcriptional activity and expression level of Cx43.

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Osterix plays a critical role in BMP4-induced promoter activity of connexin43

Han

Cho

Chung

et al. 2016

Biochemical and Biophysical Research Communications

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Liganded retinoic acid X receptor α represses connexin 43 through a potential retinoic acid response element in the promoter region

Abstract: RXRα negatively regulates the transcription and expression by directly binding to the RARE in the promoter of Cx43. The RARE-like sequence harbored in the Cx43 promoter region may serve as a functional RARE in the retinoic acid (RA) signaling pathway.

Cited by 6 publications

References 41 publications

Association ofCx43rs2071166 polymorphism with an increased risk for atrial septal defect

Association ofCx43rs2071166 polymorphism with an increased risk for atrial septal defect

The role of histone modification and a regulatory single-nucleotide polymorphism (rs2071166) in the Cx43 promoter in patients with TOF

Osterix plays a critical role in BMP4-induced promoter activity of connexin43

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