1. A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease
- Author
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Nim, HT, Dang, L, Thiyagarajah, H, Bakopoulos, D, See, M, Charitakis, N, Sibbritt, T, Eichenlaub, MP, Archer, SK, Fossat, N, Burke, RE, Tam, PPL, Warr, CG, Johnson, TK, Ramialison, M, Nim, HT, Dang, L, Thiyagarajah, H, Bakopoulos, D, See, M, Charitakis, N, Sibbritt, T, Eichenlaub, MP, Archer, SK, Fossat, N, Burke, RE, Tam, PPL, Warr, CG, Johnson, TK, and Ramialison, M
- Abstract
BACKGROUND: Congenital heart diseases are the major cause of death in newborns, but the genetic etiology of this developmental disorder is not fully known. The conventional approach to identify the disease-causing genes focuses on screening genes that display heart-specific expression during development. However, this approach would have discounted genes that are expressed widely in other tissues but may play critical roles in heart development. RESULTS: We report an efficient pipeline of genome-wide gene discovery based on the identification of a cardiac-specific cis-regulatory element signature that points to candidate genes involved in heart development and congenital heart disease. With this pipeline, we retrieve 76% of the known cardiac developmental genes and predict 35 novel genes that previously had no known connectivity to heart development. Functional validation of these novel cardiac genes by RNAi-mediated knockdown of the conserved orthologs in Drosophila cardiac tissue reveals that disrupting the activity of 71% of these genes leads to adult mortality. Among these genes, RpL14, RpS24, and Rpn8 are associated with heart phenotypes. CONCLUSIONS: Our pipeline has enabled the discovery of novel genes with roles in heart development. This workflow, which relies on screening for non-coding cis-regulatory signatures, is amenable for identifying developmental and disease genes for an organ without constraining to genes that are expressed exclusively in the organ of interest.
- Published
- 2021