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Open Access Research article

Vasohibin-1 is identified as a master-regulator of endothelial cell apoptosis using gene network analysis

Muna Affara1, Debbie Sanders1, Hiromitsu Araki2, Yoshinori Tamada3, Benjamin J Dunmore1, Sally Humphreys1, Seiya Imoto3, Christopher Savoie2, Satoru Miyano3, Satoru Kuhara4, David Jeffries5, Cristin Print67* and D Stephen Charnock-Jones18*

Author affiliations

1 Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, U.K

2 Systems Pharmacology Research Institute, GNI Ltd., Fukuoka, Japan

3 Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

4 Graduate School of Genetic Resources Technology, Kyushu University, Fukuoka, Japan

5 MRC, The Gambia Unit, Fajara, The Gambia

6 Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand

7 Bioinformatics Institute, University of Auckland, Auckland, New Zealand

8 National Institute for Health Research, Cambridge Comprehensive Biomedical Centre, Cambridge, UK

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Citation and License

BMC Genomics 2013, 14:23  doi:10.1186/1471-2164-14-23

Published: 16 January 2013

Abstract

Background

Apoptosis is a critical process in endothelial cell (EC) biology and pathology, which has been extensively studied at protein level. Numerous gene expression studies of EC apoptosis have also been performed, however few attempts have been made to use gene expression data to identify the molecular relationships and master regulators that underlie EC apoptosis. Therefore, we sought to understand these relationships by generating a Bayesian gene regulatory network (GRN) model.

Results

ECs were induced to undergo apoptosis using serum withdrawal and followed over a time course in triplicate, using microarrays. When generating the GRN, this EC time course data was supplemented by a library of microarray data from EC treated with siRNAs targeting over 350 signalling molecules.

The GRN model proposed Vasohibin-1 (VASH1) as one of the candidate master-regulators of EC apoptosis with numerous downstream mRNAs. To evaluate the role played by VASH1 in EC, we used siRNA to reduce the expression of VASH1. Of 10 mRNAs downstream of VASH1 in the GRN that were examined, 7 were significantly up- or down-regulated in the direction predicted by the GRN.Further supporting an important biological role of VASH1 in EC, targeted reduction of VASH1 mRNA abundance conferred resistance to serum withdrawal-induced EC death.

Conclusion

We have utilised Bayesian GRN modelling to identify a novel candidate master regulator of EC apoptosis. This study demonstrates how GRN technology can complement traditional methods to hypothesise the regulatory relationships that underlie important biological processes.

Keywords:
Vasohibin; HUVEC; Bayesian; Gene regulatory network