Cardiac Network Component Predictor Using cis-Regulatory Elements (CREs)
Creators
- 1. Monash University
- 2. Murdoch Children's Research Institute
- 3. University of Sydney
- 4. La Trobe University
Description
Background. Congenital heart diseases (CHD) are the major cause of death in newborns, but the genetic aetiology 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. With this pipeline, we retrieved 76% of the known cardiac developmental genes, and predicted 35 novel genes that previously have no connectivity to heart development. Functional validation of these novel cardiac genes by RNAi-mediated knockdown of the conserved orthologs in Drosophila cardiac tissue revealed that disrupting the activity of 71% of these genes led to adult mortality, and among these genes, RpL14, RpS24 and Rpn8 were 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 genes for an organ without constraining to genes that are expressed exclusively in the organ of interest.
Files
Genome-Biology.zip
Files
(114.3 MB)
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