Abstract
Understanding the regulation of development can help elucidate the pathogenesis behind many developmental defects found in humans and other vertebrates. Evidence has shown that alternative splicing of messenger RNA (mRNA) plays a role in developmental regulation, but our knowledge of the underlying mechanisms that regulate alternative splicing are incomplete. Notably, a subset of small noncoding RNAs known as scaRNAs (small cajal body associated RNAs) contribute to spliceosome maturation and function through guiding covalent modification of spliceosomal RNAs with either methylation or pseudouridylation on specific nucleotides, but the developmental significance of these modifications is not well understood. Our focus is on one such scaRNA, known as SNORD94 or U94, that guides methylation on one specific cytosine (C62) on spliceosomal RNA U6, thus potentially altering spliceosome function during embryogenesis. We previously showed that in the myocardium of infants with heart defects, mRNA is alternatively spliced as compared to control tissues. We also demonstrated that alternatively spliced genes were concentrated in the pathways that control heart development. Furthermore, we showed that modifying expression of scaRNAs alters mRNA splicing in human cells, and zebrafish embryos. Here we present evidence that SNORD94 levels directly influence levels of methylation at its target region in U6, suggesting a potential mechanism for modifying alternative splicing of mRNA. The potential importance of scaRNAs as a developmentally important regulatory mechanism controlling alternative splicing of mRNA is unappreciated and needs more research.
Highlights
Congenital heart defects are structural problems in the heart that are present at birth that affect normal function and blood flow through the heart [1]
We focused on important regulatory genes involved in heart development in particular (GATA4, MBNL1, MBNL2, DICER, DAAM1, and NOTCH2), and showed that the alternative splice isoforms of these genes were abnormal in tetralogy of Fallot (TOF) patients compared to control, and they were more similar to fetal tissue splice isoforms [8]
We have shown that methylation in the target region of SNORD94 on U6 is reduced in right ventricle tissue of children with TOF as compared to control
Summary
Congenital heart defects are structural problems in the heart that are present at birth that affect normal function and blood flow through the heart [1]. 1% of children are born with a congenital heart defect (CHD) every year, making it the most common type of birth defect [1]. Despite how common these defects are, a resounding majority (>70%) of CHDs have unknown etiology to date [2]. TOF includes pulmonary stenosis, a large ventricular septal defect, an overriding aorta, and right ventricular hypertrophy The result of this condition is oxygen-poor blood from the right ventricle being pumped into the aorta rather than the pulmonary artery, and an overworking of the right ventricle that causes the hypertrophy [1]. TOF is treated with surgical intervention, the first of which occurs within the first year of life with potential further or repeated surgeries later in life
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