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Gene expression in cardiac tissues from infants with idiopathic conotruncal defects

ABSTRACT: Tetralogy of Fallot (TOF) is the most commonly seen type of conotruncal congenital heart defect. Treatment of these patients has evolved dramatically in the last few decades, yet a genetic explanation for the failure of cardiac development is lacking for the majority of children with TOF. Our goal was to examine genome wide gene expression to characterize expression patterns in cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with tetralogy of Fallot. We employed genome wide gene expression microarrays to characterize cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with tetralogy of Fallot (16 idiopathic and 3 with 22q11.2 deletions) and compared gene expression patterns to normally developing subjects. We detected a signal from approximately 26,000 probes (ranging from 35% to 49% of array probes in the three tissues), reflecting expression from about half of all genes. More than 1000 genes had a 2-fold change in expression in the right ventricle (RV) of children with TOF compared to RV from matched control infants. Most of these genes were involved in compensatory functions (e.g., hypertrophy, cardiac fibrosis and cardiac dilation). However, two canonical pathways involved in spatial and temporal cell differentiation (WNT, p = 0.017 and Notch, p = 0.003) appeared to be generally suppressed. The suppression of developmental networks may be a remnant of a broad malfunction of regulatory pathways leading to inaccurate boundary formation and improper structural development in the embryonic heart. We suggest that small tissue specific genomic and/or epigenetic fluctuations could be cumulative, leading to regulatory network disruption and failure of proper cardiac development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26125 | GEO | 2011/01/20

SECONDARY ACCESSION(S): PRJNA135369

REPOSITORIES: GEO

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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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Gene expression in cardiac tissues from infants with idiopathic conotruncal defects

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