A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network

Gregory D Amoutzias¹^,2^,3^,4 , Elgar E Pichler³ , Nina Mian⁵ , David De Graaf³^,6 , Anastasia Imsiridou⁷ , Marc Robinson-Rechavi² , Erich Bornberg-Bauer¹^,8 , David L Robertson¹ and Stephen G Oliver¹

¹Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK

²Department of Ecology and Evolution, University of Lausanne & Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland

³Discovery Information, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA

⁴Bioinformatics & Evolutionary Genomics, Department of Plant Systems Biology, VIB/Ghent University, Technologiepark 927, B-9052 Ghent, Belgium

⁵AstraZeneca R&D, Alderley Park, UK

⁶Pfizer RTC Cambridge, Cambridge, MA, USA

⁷Higher Technological Educational Institute of Thessaloniki, 63200 Nea Moudania, Halkidiki, Greece

⁸Bioinformatics Division, Institute for Evolution and Biodiversity, School of Biological Sciences, University of Muenster, Schlossplatz 4, D48149, Muenster, Germany

author email corresponding author email

BMC Systems Biology 2007, 1:34doi:10.1186/1752-0509-1-34


Published:	31 July 2007

Abstract

Background

The nuclear receptors are a large family of eukaryotic transcription factors that constitute major pharmacological targets. They exert their combinatorial control through homotypic heterodimerisation. Elucidation of this dimerisation network is vital in order to understand the complex dynamics and potential cross-talk involved.

Results

Phylogeny, protein-protein interactions, protein-DNA interactions and gene expression data have been integrated to provide a comprehensive and up-to-date description of the topology and properties of the nuclear receptor interaction network in humans. We discriminate between DNA-binding and non-DNA-binding dimers, and provide a comprehensive interaction map, that identifies potential cross-talk between the various pathways of nuclear receptors.

Conclusion

We infer that the topology of this network is hub-based, and much more connected than previously thought. The hub-based topology of the network and the wide tissue expression pattern of NRs create a highly competitive environment for the common heterodimerising partners. Furthermore, a significant number of negative feedback loops is present, with the hub protein SHP [NR0B2] playing a major role. We also compare the evolution, topology and properties of the nuclear receptor network with the hub-based dimerisation network of the bHLH transcription factors in order to identify both unique themes and ubiquitous properties in gene regulation. In terms of methodology, we conclude that such a comprehensive picture can only be assembled by semi-automated text-mining, manual curation and integration of data from various sources.