O'Brien James E, Kibiryeva Nataliya, Zhou Xin-Gang, Marshall Jennifer A, Lofland Gary K, Artman Michael, Chen Jie, Bittel Douglas C
Section of Cardiovascular and Thoracic Surgery, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA.
Circ Cardiovasc Genet. 2012 Jun;5(3):279-86. doi: 10.1161/CIRCGENETICS.111.961474. Epub 2012 Apr 23.
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.
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.
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.
非编码RNA（ncRNA），尤其是微小RNA（miRNA），对于维持发育中的脊椎动物心脏的稳定性的重要性最近已变得明显；然而，关于ncRNA在患有发育异常的人类心脏中的表达模式却知之甚少。
我们检测了16例无22q11.2缺失的非综合征性法洛四联症（TOF）婴儿的右心室心肌、3份胎儿心脏样本以及8例正常发育婴儿的右心室心肌中miRNA和小核仁RNA（snoRNA）的表达。我们发现与正常发育的对照受试者相比，TOF患儿心肌中61种miRNA和135种snoRNA的表达有显著变化。TOF心肌中ncRNA的表达模式与胎儿心肌中的表达模式惊人地相似，尤其是snoRNA。表达改变的miRNA的潜在靶标在对心脏发育重要的基因网络中富集。我们列出了已知对心脏发育至关重要的229个基因的清单，发现其中44个基因在TOF心肌中的表达相对于正常发育的心肌有显著变化。这44个基因与33种miRNA呈显著负相关，而这些miRNA的表达也均有显著变化。snoRNA的主要功能是靶向核糖体RNA和剪接体RNA的特定核苷酸进行生化修饰。差异表达的snoRNA的靶向核苷酸集中在28S和18S核糖体RNA以及2种剪接体RNA，即U2和U6中。此外，在TOF患儿的心肌中，我们观察到对心脏发育至关重要的基因中有51%存在剪接变体。综上所述，这些观察结果表明靶向剪接体RNA的snoRNA水平、剪接体功能与心脏发育之间存在联系。
这是首篇描述先天性心脏缺陷中ncRNA表达的报告。ncRNA表达的显著变化反映了细胞生物学的根本变化，可能影响发育重要基因的表达、转录剪接和翻译，并可能导致心脏缺陷。
