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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease. / Nim, Hieu T.; Dang, Louis; Thiyagarajah, Harshini; Bakopoulos, Daniel; See, Michael; Charitakis, Natalie; Sibbritt, Tennille; Eichenlaub, Michael P.; Archer, Stuart K.; Fossat, Nicolas; Burke, Richard E.; Tam, Patrick P.L.; Warr, Coral G.; Johnson, Travis K.; Ramialison, Mirana.

In: Genome Biology, Vol. 22, 335, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 2021, 'A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease', Genome Biology, vol. 22, 335. https://doi.org/10.1186/s13059-021-02539-0

APA

Nim, H. T., Dang, L., Thiyagarajah, H., Bakopoulos, D., See, M., Charitakis, N., Sibbritt, T., Eichenlaub, M. P., Archer, S. K., Fossat, N., Burke, R. E., Tam, P. P. L., Warr, C. G., Johnson, T. K., & Ramialison, M. (2021). A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease. Genome Biology, 22, [335]. https://doi.org/10.1186/s13059-021-02539-0

Vancouver

Nim HT, Dang L, Thiyagarajah H, Bakopoulos D, See M, Charitakis N et al. A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease. Genome Biology. 2021;22. 335. https://doi.org/10.1186/s13059-021-02539-0

Author

Nim, Hieu T. ; Dang, Louis ; Thiyagarajah, Harshini ; Bakopoulos, Daniel ; See, Michael ; Charitakis, Natalie ; Sibbritt, Tennille ; Eichenlaub, Michael P. ; Archer, Stuart K. ; Fossat, Nicolas ; Burke, Richard E. ; Tam, Patrick P.L. ; Warr, Coral G. ; Johnson, Travis K. ; Ramialison, Mirana. / A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease. In: Genome Biology. 2021 ; Vol. 22.

Bibtex

@article{78830ea6bf814693b58b1e06858a05d2,
title = "A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease",
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.",
keywords = "Computational genomics, Congenital heart disease, Drosophila, Heart development, Regulatory elements, RNAi, Tissue-specific expression",
author = "Nim, {Hieu T.} and Louis Dang and Harshini Thiyagarajah and Daniel Bakopoulos and Michael See and Natalie Charitakis and Tennille Sibbritt and Eichenlaub, {Michael P.} and Archer, {Stuart K.} and Nicolas Fossat and Burke, {Richard E.} and Tam, {Patrick P.L.} and Warr, {Coral G.} and Johnson, {Travis K.} and Mirana Ramialison",
note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
doi = "10.1186/s13059-021-02539-0",
language = "English",
volume = "22",
journal = "Genome Biology (Online Edition)",
issn = "1474-7596",
publisher = "BioMed Central Ltd.",

}

RIS

TY - JOUR

T1 - A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease

AU - Nim, Hieu T.

AU - Dang, Louis

AU - Thiyagarajah, Harshini

AU - Bakopoulos, Daniel

AU - See, Michael

AU - Charitakis, Natalie

AU - Sibbritt, Tennille

AU - Eichenlaub, Michael P.

AU - Archer, Stuart K.

AU - Fossat, Nicolas

AU - Burke, Richard E.

AU - Tam, Patrick P.L.

AU - Warr, Coral G.

AU - Johnson, Travis K.

AU - Ramialison, Mirana

N1 - Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Computational genomics

KW - Congenital heart disease

KW - Drosophila

KW - Heart development

KW - Regulatory elements

KW - RNAi

KW - Tissue-specific expression

U2 - 10.1186/s13059-021-02539-0

DO - 10.1186/s13059-021-02539-0

M3 - Journal article

C2 - 34906219

AN - SCOPUS:85121312445

VL - 22

JO - Genome Biology (Online Edition)

JF - Genome Biology (Online Edition)

SN - 1474-7596

M1 - 335

ER -

ID: 288120807