CpG island shore methylation of ZFPM2 is identified in tetralogy of fallot samples

Wei, Sheng; Chen, Long; Wang, Huijun; Ma, Xiaojing; Ma, Ding; Huang, Guoying

doi:10.1038/pr.2016.42

Cited by 15 publications

(19 citation statements)

References 31 publications

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“…NOTCH1 was identified as the major cardiac damaging gene, and there were methylation changes in the NOTCH pathway, such as IDB4 ( Greenway et al, 2009 ). Additionally, some studies revealed that both gene mutations and methylation modifications account for the development of CHD, such as CITED2 mutations along with promoter region methylation ( Xu et al, 2014 ; Sheng et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The Interaction Analysis of SNP Variants and DNA Methylation Identifies Novel Methylated Pathogenesis Genes in Congenital Heart Diseases

Wang¹,

Ma²,

Zhang³

et al. 2021

Front. Cell Dev. Biol.

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Congenital heart defect (CHD) is a rare and complicated disease with a high mortality rate. Its etiology remains unclear and includes many aspects. DNA methylation has been indicated to be involved in heart development in the early stage of life, and aberrant methylation level was related to CHDs. This study provides the first evidence of the cross talk of SNP variants and DNA methylation in clarifying CHD underlying genomic cause. We gathered whole exome sequencing (WES) data for Group 1 consisting of patients with PA (n = 78), TOF (n = 20), TAPVC (n = 78), and PDA (n = 40), and 100 healthy children as control group. Rare non-synonymous mutations and novel genes were found and highlighted. Meanwhile, we carried out the second analysis of DNA methylation data from patients with PA (n = 3), TAPVC (n = 3), TOF (n = 3), and PDA (n = 2), and five healthy controls using 850 K array in Group 2. DNA methylation was linked to WES data, and we explored an obvious overlap of hyper/hypomethylated genes. Next, we identified some candidate genes by Fisher’s exact test and Burden analysis; then, those methylated genes were figured out by the criteria of the mutation located in the CpG islands of the genome, differential methylation sites (DMS), and DNA methylation quantitative trait loci (meQTLs) in the database, respectively. Also, the interaction of differentially methylated candidate genes with known CHD pathogenetic genes was depicted in a molecular network. Taken together, our findings show that nine novel genes (ANGPTL4, VEGFA, PAX3, MUC4, HLA-DRB1, TJP2, BCR, PKD1, and HK2) in methylation level are critical to CHD and reveal a new insight into the molecular pathogenesis of CHD.

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Section: Introductionmentioning

confidence: 99%

The Interaction Analysis of SNP Variants and DNA Methylation Identifies Novel Methylated Pathogenesis Genes in Congenital Heart Diseases

Wang¹,

Ma²,

Zhang³

et al. 2021

Front. Cell Dev. Biol.

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“…The ZFPM2 gene plays an important role in heart morphogenesis and the development of coronary vessels from the epicardium. The methylation levels of the CpG island shore in the ZFPM2 promoter were significantly higher in patients with TOF than in controls and were negatively associated with significant changes in its mRNA level [11].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation status of TBX20 in patients with tetralogy of Fallot

Gong

Sheng

Ma³

et al. 2019

BMC Med Genomics

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Background TBX20 plays an important role in heart development; however, its epigenetic regulation in the pathogenesis of tetralogy of Fallot (TOF) remains unclear. Methods The methylation levels of the TBX20 promoter region in the right ventricular myocardial tissues of TOF and control samples were measured by the Sequenom MassARRAY platform. Bisulphite-sequencing PCR (BSP) was used to confirm the TBX20 methylation of CpG sites in cells. Dual-luciferase reporter assays were performed to detect the influence of TBX20 methylation and Sp1 transcription factors on gene activity. An electrophoretic mobility shift assay (EMSA) was used to explore the binding of the Sp1 transcription factor to the TBX20 promoter. Results TOF cases had a significantly lower TBX20 _M1 methylation level than controls (median methylation: 20.40% vs. 38.73%; p = 0.0047). The Sp1 transcription factor, which binds to Sp1 binding sites in the TBX20 _M1 region and promotes TBX20 gene activity, was blocked by the methylation of Sp1 binding sites in normal controls. With decreasing methylation in the TOF cases, the Sp1 transcription factor can bind to its binding site within the TBX20 promoter M1 region and promote TBX20 gene expression. Conclusions Hypomethylation of the TBX20 promoter region was observed in the TOF cases, and the high expression of the TBX20 gene may be caused by activated Sp1 transcription factor binding because of the decreasing methylation at the Sp1 transcription factor binding sites within TBX20_M1.

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“…ZFPM2 encodes transcription factors that are essential for ventricular septum or outflow tract morphogenesis in heart development that can physically interact with GATA4 to modulate the transcription of target genes (Bruneau, ; Hirai et al, ). GATA4 and ZFPM2 are widely recognized as being associated with congenital heart diseases (Sheng et al, ; Zhang et al, ). The interaction binding of GATA4 and ZFPM2 protein serves not only to coregulate gene expression but also to prevent transcription factors from distributing to ectopic loci and activating lineage‐inappropriate genes (Luna‐Zurita et al, ).…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect

Zhao

Zhan

Chen

et al. 2019

Genesis

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Summary Congenital heart defect (CHD) is one of the most common cardiovascular diseases, affecting approximately 0.8% of live births. The transcription factor GATA4 has been known to play a key role in cardiac development. In this study, we performed whole exome sequencing in nine unrelated CHD patients and found two rare deleterious missense variants in the GATA4 gene (c.C487T,p.P163S and c.C1223A,p.P408Q) (ExAC <0.001 and CADD >15) in three cases that were confirmed by Sanger sequencing. Subsequently, these two variants were screened for in an additional 226 patients with CHD and 206 healthy controls by Sanger sequencing, and no variants were observed. These two variants were predicted to be damaging to protein function using a functional prediction program. Co‐IP indicated that both of the GATA4 variants (P163S and P408Q) blocked heterodimer formation between GATA4 and ZFPM2 protein. Immunofluorescence showed that the two GATA4 variants diminished the colocalization formation between GATA4 and ZFPM2 protein compared to that of WT protein. These findings indicate that the two rare variants of GATA4 might disturb its interaction with ZFPM2 and influence corresponding downstream gene activity, suggesting that the GATA4 variants may be associated with the pathogenesis of CHD.

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CpG island shore methylation of ZFPM2 is identified in tetralogy of fallot samples

Cited by 15 publications

References 31 publications

The Interaction Analysis of SNP Variants and DNA Methylation Identifies Novel Methylated Pathogenesis Genes in Congenital Heart Diseases

The Interaction Analysis of SNP Variants and DNA Methylation Identifies Novel Methylated Pathogenesis Genes in Congenital Heart Diseases

DNA methylation status of TBX20 in patients with tetralogy of Fallot

Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect

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