Noncoding RNA expression in myocardium from infants with tetralogy of fallot

James E. O'Brien, Nataliya Kibiryeva, Xin Gang Zhou, Jennifer A. Marshall, Gary K. Lofland, Michael Artman, Jie Chen, Douglas C. Bittel

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background- The importance of noncoding RNAs (ncRNA), especially microRNAs (miRNAs), 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. Methods and Results- We examined the expression of miRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, 3 fetal heart samples, and 8 normally developing infants. We found 61 miRNAs and 135 snoRNAs to be significantly changed in expression in myocardium from children with TOF compared with normally developing comparison subjects. The pattern of ncRNA expression in TOF myocardium had a surprising resemblance to expression patterns in fetal myocardium, especially for the snoRNAs. Potential targets of miRNAs 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 miRNAs, 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 2 spliceosomal RNAs, U2 and U6. In addition, in myocardium from children with TOF, we observed splicing variants in 51% of genes that are critical for cardiac development. Taken together, these observations suggest a link between levels of snoRNA that target spliceosomal RNAs, spliceosomal function, and heart development. Conclusions- This is the first report characterizing ncRNA expression in a congenital heart defect. The striking shift in expression of ncRNAs 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.

Original languageEnglish (US)
Pages (from-to)279-286
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number3
DOIs
StatePublished - Jun 1 2012

Fingerprint

Small Nucleolar RNA
Untranslated RNA
Tetralogy of Fallot
Myocardium
MicroRNAs
Genes
28S Ribosomal RNA
Nucleotides
18S Ribosomal RNA
RNA
Fetal Heart
Ribosomal RNA
Congenital Heart Defects
Gene Regulatory Networks
Cell Biology
Vertebrates

Keywords

  • Cardiac development
  • MiRNA
  • MicroRNA
  • Small nucleolar RNA
  • SnoRNA
  • Tetralogy of Fallot

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

O'Brien, J. E., Kibiryeva, N., Zhou, X. G., Marshall, J. A., Lofland, G. K., Artman, M., ... Bittel, D. C. (2012). Noncoding RNA expression in myocardium from infants with tetralogy of fallot. Circulation: Cardiovascular Genetics, 5(3), 279-286. https://doi.org/10.1161/CIRCGENETICS.111.961474

Noncoding RNA expression in myocardium from infants with tetralogy of fallot. / O'Brien, James E.; Kibiryeva, Nataliya; Zhou, Xin Gang; Marshall, Jennifer A.; Lofland, Gary K.; Artman, Michael; Chen, Jie; Bittel, Douglas C.

In: Circulation: Cardiovascular Genetics, Vol. 5, No. 3, 01.06.2012, p. 279-286.

Research output: Contribution to journalArticle

O'Brien, JE, Kibiryeva, N, Zhou, XG, Marshall, JA, Lofland, GK, Artman, M, Chen, J & Bittel, DC 2012, 'Noncoding RNA expression in myocardium from infants with tetralogy of fallot', Circulation: Cardiovascular Genetics, vol. 5, no. 3, pp. 279-286. https://doi.org/10.1161/CIRCGENETICS.111.961474
O'Brien, James E. ; Kibiryeva, Nataliya ; Zhou, Xin Gang ; Marshall, Jennifer A. ; Lofland, Gary K. ; Artman, Michael ; Chen, Jie ; Bittel, Douglas C. / Noncoding RNA expression in myocardium from infants with tetralogy of fallot. In: Circulation: Cardiovascular Genetics. 2012 ; Vol. 5, No. 3. pp. 279-286.
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AB - Background- The importance of noncoding RNAs (ncRNA), especially microRNAs (miRNAs), 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. Methods and Results- We examined the expression of miRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, 3 fetal heart samples, and 8 normally developing infants. We found 61 miRNAs and 135 snoRNAs to be significantly changed in expression in myocardium from children with TOF compared with normally developing comparison subjects. The pattern of ncRNA expression in TOF myocardium had a surprising resemblance to expression patterns in fetal myocardium, especially for the snoRNAs. Potential targets of miRNAs 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 miRNAs, 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 2 spliceosomal RNAs, U2 and U6. In addition, in myocardium from children with TOF, we observed splicing variants in 51% of genes that are critical for cardiac development. Taken together, these observations suggest a link between levels of snoRNA that target spliceosomal RNAs, spliceosomal function, and heart development. Conclusions- This is the first report characterizing ncRNA expression in a congenital heart defect. The striking shift in expression of ncRNAs 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.

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