A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Full text
Forlagets udgivne version, 2,67 MB, PDF-dokument
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 335 |
| Tidsskrift | Genome Biology |
| Vol/bind | 22 |
| ISSN | 1474-7596 |
| DOI | |
| Status | Udgivet - 2021 |
| Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
We thank Jeannette Hallab, Markus Tondl, Mark Drvodelic, Henry Chiu, Julian Stolper, Denis Bienroth, and all the members of the Ramialison laboratory for their support and feedback. We thank the Monash eResearch platform for their support with the server, the Australian Drosophila Biomedical Research Facility (OzDros) for fly stock importation, and the Vienna Drosophila Resource Center, Darshana Vadgama for technical assistance, and Zhe Han for fly stocks. We thank Robert Bryson-Richardson, Peter Currie, Kelly Smith, Guillaume Junion, Mauro Costa, Milena Furtado, and Nadia Rosenthal for their critical input. The review history is available as Additional file 3. Tim Sands was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Funding Information:
This work was supported by the Australian Research Council Discovery Project grants DP140101067; a National Health and Medical Research Council (NHMRC)/Heart Foundation Career Development Fellowship (1049980), NHMRC Ideas Grant (APP1180905) and Sun foundation to M.R.; NHMRC Ideas grant (1182330) to T.K.J and Australian Research Council Discovery Project grant (DP160100933) to P.P.L.T. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. This work was further supported by the Monash University Science-Medicine, Nursing, and Health Science Faculties Interdisciplinary Research Scheme.
Publisher Copyright:
© 2021, The Author(s).
ID: 288120807