Unknown,Transcriptomics,Genomics,Proteomics

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Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases

ABSTRACT: The most common congenital heart disease (CHD) is the ventricular septal defect (VSD), which is also a subfeature of Tetralogy of Fallot (TOF) representing the most common form of cyanotic CHD. The underlying causes for the majority of CHDs are still unclear and most probably consist of combinations of genetic, epigenetic and environmental factors. DNA methylation is the most widely studied epigenetic modification and several cardiac regulators have already been shown to be differentially methylated in CHD patients. Here, we present the first analysis of genome-wide DNA methylation data obtained from cardiac biopsies of TOF and VSD patients. We applied affinity-based enrichment of methylated DNA sequences with methyl-CpG-binding domain proteins followed by next-generation sequencing (MBD-Seq). MBD-seq on cardiac biopsies of patients with Tetralogy of Fallot and ventricular septal defect

ORGANISM(S): Homo sapiens

SUBMITTER: Silke Sperling

PROVIDER: E-GEOD-62629 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:This is the first report characterizing noncoding RNA expression in a congenital heart defect. The striking shift in expression of noncoding RNAs reflects a fundamental change in cell biology, likely impacting expression, transcript splicing and translation of developmentally important genes and possibly contributing to the cardiac defect. The importance of noncoding RNAs (ncRNA), especially microRNAs, for maintaining stability in the developing vertebrate heart has recently become apparent. However, there is little known about the expression pattern of ncRNA in the human heart with developmental anomalies. We examined the expression of microRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, three fetal heart samples and eight normally developing infants. We found 61 microRNAs and 135 snoRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects. The pattern of ncRNA expression in TOF myocardium had a remarkable resemblance to expression patterns in fetal myocardium, especially for the snoRNAs. Potential targets of microRNAs with altered expression were enriched for gene networks of importance to cardiac development. We derived a list of 229 genes known to be critical to heart development and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlation with 33 microRNAs, each of which also had significantly changed expression. The primary function of snoRNAs is targeting specific nucleotides of ribosomal RNAs and spliceosomal RNAs for biochemical modification. The targeted nucleotides of the differentially expressed snoRNAs were concentrated in the 28S and 18S ribosomal RNAs and two spliceosomal RNAs, U2 and U6. In addition, in myocardium from children with TOF, we observed splicing variants in 51% of the critical cardiac developmental genes. Taken together, these observations suggest a link between snoRNA level in the myocardium, spliceosomal function and heart development. We examined the expression of microRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, three fetal heart samples and eight normally developing infants

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Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases

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