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Open Access Research article

Identification of cis-regulatory modules encoding temporal dynamics during development

Delphine Potier124, Denis Seyres12, Céline Guichard12, Magali Iche-Torres12, Stein Aerts4, Carl Herrmann125* and Laurent Perrin123*

Author Affiliations

1 INSERM, UMR1090 TAGC, Marseille F-13288, France

2 Aix-Marseille Université, UMR1090 TAGC, Marseille F-13288, France

3 CNRS, Marseille, France

4 Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, Herestraat 49, P.O. Box 602 3000 Leuven, Belgium

5 IPMB, University of Heidelberg and German Cancer Research Center, div. of Theoretical Bioinformatics, Im Neuenheimer Feld 280, Heidelberg 69120, Germany

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BMC Genomics 2014, 15:534  doi:10.1186/1471-2164-15-534

Published: 27 June 2014

Abstract

Background

Developmental transcriptional regulatory networks are circuits of transcription factors (TFs) and cis-acting DNA elements (Cis Regulatory Modules, CRMs) that dynamically control expression of downstream genes. Comprehensive knowledge of these networks is an essential step towards our understanding of developmental processes. However, this knowledge is mostly based on genome-wide mapping of transcription factor binding sites, and therefore requires prior knowledge regarding the TFs involved in the network.

Results

Focusing on how temporal control of gene expression is integrated within a developmental network, we applied an in silico approach to discover regulatory motifs and CRMs of co-expressed genes, with no prior knowledge about the involved TFs. Our aim was to identify regulatory motifs and potential trans-acting factors which regulate the temporal expression of co-expressed gene sets during a particular process of organogenesis, namely adult heart formation in Drosophila. Starting from whole genome tissue specific expression dynamics, we used an in silico method, cisTargetX, to predict TF binding motifs and CRMs. Potential Nuclear Receptor (NR) binding motifs were predicted to control the temporal expression profile of a gene set with increased expression levels during mid metamorphosis. The predicted CRMs and NR motifs were validated in vivo by reporter gene essays. In addition, we provide evidence that three NRs modulate CRM activity and behave as temporal regulators of target enhancers.

Conclusions

Our approach was successful in identifying CRMs and potential TFs acting on the temporal regulation of target genes. In addition, our results suggest a modular architecture of the regulatory machinery, in which the temporal and spatial regulation can be uncoupled and encoded by distinct CRMs.

Keywords:
Cis-regulatory modules; Temporal control; Motif discovery; Transcription; Drosophila metamorphosis; Cardiogenesis