A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease

Genome Biology

Michael P. Eichenlaub¹  Louis Dang¹  Hieu T. Nim²  Mirana Ramialison²  Tennille Sibbritt³  Patrick P. L. Tam³  Nicolas Fossat⁴  Stuart K. Archer⁵  Natalie Charitakis⁶  Michael See⁷  Harshini Thiyagarajah⁸  Daniel Bakopoulos⁸  Travis K. Johnson⁸  Richard E. Burke⁸  Coral G. Warr⁹ 

[1] Australian Regenerative Medicine Institute and Systems Biology Institute Australia, Monash University, Clayton, VIC, Australia;Australian Regenerative Medicine Institute and Systems Biology Institute Australia, Monash University, Clayton, VIC, Australia;Murdoch Children’s Research Institute, Parkville, VIC, Australia;Embryology Research Unit, Children’s Medical Research Institute, and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia;Embryology Research Unit, Children’s Medical Research Institute, and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia;Present address: Copenhagen Hepatitis C Program, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;Present address: Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark;Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia;Murdoch Children’s Research Institute, Parkville, VIC, Australia;Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia;Murdoch Children’s Research Institute, Parkville, VIC, Australia;Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia;School of Biological Sciences, Faculty of Science, Monash University, Clayton, VIC, Australia;School of Biological Sciences, Faculty of Science, Monash University, Clayton, VIC, Australia;School of Molecular Sciences, La Trobe University, 3083, Bundoora, Victoria, Australia;

关键词: Regulatory elements;    Congenital heart disease;    Heart development;    Tissue-specific expression;    Computational genomics;    Drosophila;    RNAi;   

DOI  :  10.1186/s13059-021-02539-0

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY