Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

Wei, Sheng; Qian, Yanyan; Zhang, Ping; Wang, Huijun; Ma, Xiaojing; Chen, Long; Ma, Ding; Huang, Guoying

doi:10.1186/1479-5876-12-31

Cited by 43 publications

(45 citation statements)

References 43 publications

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“…Disruption of this tightly‐regulated region, as seen in our patient, may impair RXRA expression and disrupt gene‐specific signal transduction pathways. Epigenetic studies in patients with TOF demonstrate elevated promoter and LINE‐1 methylation resulting in down‐regulation of RXRA expression [Sheng et al, , ; Zhang et al, ]. The duplicated interval containing exons 2–10 seen in our patient also contains multiple repeat elements including SINEs, LINEs, and DNA transposons (MLT1D, MER103C, Charlie18a) (Fig.…”

Section: Discussionmentioning

confidence: 61%

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome

Amarillo

O’Connor

Lee

et al. 2015

American J of Med Genetics Pt A

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Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD.

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Section: Discussionmentioning

confidence: 61%

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome

Amarillo

O’Connor

Lee

et al. 2015

American J of Med Genetics Pt A

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show abstract

“…DNA methylation is a dynamic process and methylated cytosine can be oxidized to 5hmC by Tet 23 ; to understand the role of Tet in the metabolic memory phenomenon, gene transcription of Tet2 (the only member of the Tet family upregulated in the retina in diabetes 22 ), was quantified. Consistent with Dnmt1 , Tet2 transcripts also remained elevated even after 4 days of normal glucose that had followed 4 days of high glucose; but extending the normal glucose phase to 8 days (4d-8d), had significant beneficial effects on Tet2 transcripts (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DNA is “highly dynamic” and responds to the environmental stimuli by modifying its properties in adapting to the changes, 23 and DNA methylation and the changes brought by this can last for several years. 24 Our hypothesis is that DNA methylation machinery continues to function aberrantly even after the hyperglycemic insult is terminated, and here we aim to investigate the role of DNA methylation machinery in the metabolic memory phenomenon.…”

mentioning

confidence: 99%

The Role of DNA Methylation in the Metabolic Memory Phenomenon Associated With the Continued Progression of Diabetic Retinopathy

Mishra

Kowluru

2016

Invest. Ophthalmol. Vis. Sci.

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PurposeClinical and experimental studies have shown that diabetic retinopathy progression does not halt after termination of hyperglycemia, suggesting a “metabolic memory” phenomenon. DNA is highly dynamic, and cytosine methylation changes can last for several years. In diabetes, DNA methylation regulates expression of many genes associated with retinal mitochondrial homeostasis. Our aim was to investigate the role of DNA methylation in the metabolic memory.MethodsReversal of 4 days of 20 mM glucose by 4 to 8 days of 5 mM glucose, in the presence/absence of Dnmt inhibitor (5-aza-2′-deoxycytidine), was investigated on DNA methylation and its machinery in human retinal endothelial cells. The key parameters were confirmed in the retina from diabetic rats maintained in good glycemic control (glycated hemoglobin ∼6%) for 3 months after 3 months of poor control (glycated hemoglobin >10%).ResultsDNA methyltransferase 1 (Dnmt 1) remained active after 4 days of normal glucose that followed 4 days of high glucose, and mtDNA stayed hypermethylated with impaired transcription. Hydroxymethylating enzyme Tet2, and matrix metalloproteinase-9 (regulated by hydroxymethylation) also remained upregulated. But, 8 days of normal glucose after 4 days of high glucose ameliorated mtDNA methylation and MMP-9 hydroxymethylation. Direct Dnmt targeting by Aza during the reversal period benefited methylation status of mtDNA and MMP-9 DNA. Similarly, reinstitution of good control after 3 months of poor control in rats did not reverse diabetes-induced increase in retinal Dnmt1 and Tet2, and alter the methylation status of mtDNA and MMP-9.ConclusionsRetinal DNA methylation-hydroxymethylation machinery does not benefit immediately from reversal of hyperglycemia. Maintenance of good glycemic control for longer duration, and/or direct targeting DNA methylation ameliorates continuous mitochondrial damage, and could retard/halt diabetic retinopathy progression.

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“…An increase in DNA methylation can result in the binucleation and terminal differentiation of cultured fetal cardiomyocytes . Changes in methylation states at promoters of genes involved in cardiac development, including EGFR, Tbx5, and Nkx2–5, have been observed in congenital heart disease cases . These findings implicate DNA methylation as an important regulator of cardiovascular development worthy of further exploration.…”

Section: Dna Methylationmentioning

confidence: 91%

How the proteome packages the genome for cardiovascular development

Karbassi

Vondriska

2014

Proteomics

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The devastating impact of congenital heart defects has made mechanisms of vertebrate heart and vascular development an active area of study. Because myocyte death is a common feature of acquired cardiovascular diseases and the adult heart does not regenerate, the need exists to understand whether features of the developing heart and vasculature—which are more plastic—can be exploited therapeutically in the disease setting. We know that a core network of transcription factors governs commitment to the cardiovascular lineage, and recent studies using genetic loss-of-function approaches and unbiased genomic studies have revealed the role for various chromatin modulatory events. We reason that chromatin structure itself is a causal feature that influences transcriptome complexity along a developmental continuum, and the purpose of this article is to highlight the areas in which ‘omics technologies have the potential to reveal new principles of phenotypic plasticity in development. We review the major mechanisms of chromatin structural regulation, highlighting what is known about their actions to control cardiovascular differentiation. We discuss emergent mechanisms of regulation that have been identified on the basis of genomic and proteomic studies of cardiac nuclei and identify current challenges to an integrated understanding of chromatin structure and cardiovascular phenotype.

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Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

Cited by 43 publications

References 43 publications

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome

The Role of DNA Methylation in the Metabolic Memory Phenomenon Associated With the Continued Progression of Diabetic Retinopathy

How the proteome packages the genome for cardiovascular development

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