Abstract
Congenital heart disease (CHD) is a leading cause of death in children <1 year of age. Despite intense effort in the last 10 years, most CHDs (~70%) still have an unknown etiology. Conotruncal based defects, such as Tetralogy of Fallot (TOF), a common complex of devastating heart defects, typically requires surgical intervention in the first year of life. We reported that the noncoding transcriptome in myocardial tissue from children with TOF is characterized by significant variation in levels of expression of noncoding RNAs, and more specifically, a significant reduction in 12 small cajal body-associated RNAs (scaRNAs) in the right ventricle. scaRNAs are essential for the biochemical modification and maturation of small nuclear RNAs (spliceosomal RNAs), which in turn are critical components of the spliceosome. This is particularly important because we also documented that splicing of mRNAs that are critical for heart development was dysregulated in the heart tissue of infants with TOF. Furthermore, we went on to show, using the zebrafish model, that altering the expression of these same scaRNAs led to faulty mRNA processing and heart defects in the developing embryo. This review will examine how scaRNAs may influence spliceosome fidelity in exon retention during heart development and thus contribute to regulation of heart development.
Highlights
Congenital heart defects (CHD) constitute a major proportion of clinically significant birth defects worldwide [1,2]
Studies have shown that mRNA splicing of the vertebrate heart is highly dynamic and intricately regulated during embryonic heart development [3,10,11,12], but no direct link has been shown between alternative splicing and CHDs
Twelve small cajal body-associated RNAs (scaRNAs) are reduced in the right ventricle of infants with Tetralogy of Fallot (TOF) and these 12 scaRNAs target only U2 and U6
Summary
Congenital heart defects (CHD) constitute a major proportion of clinically significant birth defects worldwide [1,2]. A class of ncRNAs, the small nucleolar RNAs (snoRNAs), have been evolutionarily conserved in all eukaryotes Their canonical function is to facilitate biochemical modification of specific nucleotides (i.e., methylation and pseudouridylation) of ribosomal RNAs and spliceosomal RNAs (snRNAs, referred to as small nuclear RNAs). A class of snoRNAs called scaRNAs (small cajal body specific RNAs) target the snRNAs that are centrally important for the function of the spliceosome [25]. We hypothesized that reduced levels in scaRNAs could have an impact on spliceosome function, resulting in dysregulation of mRNA splicing that could in turn impair heart development. We used human primary cells from the right ventricle of infants with TOF and from normally developing infant heart tissue to investigate the impact of scaRNA expression level on mRNA splicing in vitro. We altered scaRNA levels in zebrafish embryos to assess the impact of altered scaRNA expression on mRNA splicing and development in vivo
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