Abstract
BackgroundCongenital 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Congenital heart diseases are the major cause of death in newborns, but the genetic etiology of this developmental disorder is not fully known
Regulatory-based bioinformatics analyses revealed novel cardiac-specific cis-regulatory elements RNA-sequencing of embryonic mouse hearts revealed that there are thousands of genes expressed in the heart at any given developmental time point
To identify which of these genes are required for cardiac development or disease, we hypothesized that these cardiac gene regulatory network (GRN) components will contain in their regulatory input one or several cardiacspecific cis-regulatory elements (CREs) that are activated in the heart
Summary
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. This approach would have discounted genes that are expressed widely in other tissues but may play critical roles in heart development. Genetic and genomics studies of CHD frequently necessitate identifying genes critical for cardiac development and function based on their heartspecific spatial expression patterns revealed, for example, by in situ hybridization, and spatially (tissue)-resolved RNA-sequencing (RNA-seq) analysis). Located at the core of the GRN, the kernel comprises several transcription factors (TFs), such as NKX2-5, TBX5, and GATA4 [2], that act as key regulators serving to integrate crossregulatory interactions and drive the expression of TF-related target genes. Binding of TFs to their target genes, through sequence-specific transcription factor binding sites (TFBS) in the CREs, regulates the expression of the target genes at the precise time and location during development
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