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

BackgroundThe 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.ResultsPhylogeny, 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.ConclusionWe 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.

[1]  Erich Bornberg-Bauer,et al.  Reduction/oxidation-phosphorylation control of DNA binding in the bZIP dimerization network , 2006, BMC Genomics.

[2]  V. Giguère,et al.  Orphan nuclear receptors: from gene to function. , 1999 .

[3]  Vincent Laudet,et al.  International Union of Pharmacology. LXVI. Orphan Nuclear Receptors , 2006, Pharmacological Reviews.

[4]  Richard A. Heyman,et al.  Orphan Nuclear Receptors , 2000 .

[5]  Yueh-Chiang Hu,et al.  Modulation of Estrogen Receptor-mediated Transactivation by Orphan Receptor TR4 in MCF-7 Cells* , 2002, The Journal of Biological Chemistry.

[6]  Gregor Eichele,et al.  International Union of Pharmacology. LXIII. Retinoid X Receptors , 2006, Pharmacological Reviews.

[7]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[8]  K. Umesono,et al.  Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors. , 1996, Molecular endocrinology.

[9]  Kumaran Kandasamy,et al.  An evaluation of human protein-protein interaction data in the public domain , 2006, BMC Bioinformatics.

[10]  E. Bornberg-Bauer,et al.  One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity. , 2006, Molecular biology and evolution.

[11]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[12]  A. Keating,et al.  Comprehensive Identification of Human bZIP Interactions with Coiled-Coil Arrays , 2003, Science.

[13]  Erich Bornberg-Bauer,et al.  Convergent evolution of gene networks by single‐gene duplications in higher eukaryotes , 2004, EMBO reports.

[14]  Albert-László Barabási,et al.  Error and attack tolerance of complex networks , 2000, Nature.

[15]  S. Schreiber,et al.  Dimerization as a regulatory mechanism in signal transduction. , 1998, Annual review of immunology.

[16]  R. Tjian,et al.  Transcription regulation and animal diversity , 2003, Nature.

[17]  Dipanwita Roy Chowdhury,et al.  Human protein reference database as a discovery resource for proteomics , 2004, Nucleic Acids Res..

[18]  D. Fell,et al.  The small world inside large metabolic networks , 2000, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[19]  Vincent Laudet,et al.  Principles for modulation of the nuclear receptor superfamily , 2004, Nature Reviews Drug Discovery.

[20]  A. Dunker,et al.  Disorder and sequence repeats in hub proteins and their implications for network evolution. , 2006, Journal of proteome research.

[21]  Erich Bornberg-Bauer,et al.  The Evolution of Protein Interaction Networks in Regulatory Proteins , 2004, Comparative and functional genomics.

[22]  Béatrice Desvergne,et al.  RXR: from partnership to leadership in metabolic regulations. , 2007, Vitamins and hormones.

[23]  D. Moore,et al.  An Orphan Nuclear Hormone Receptor That Lacks a DNA Binding Domain and Heterodimerizes with Other Receptors , 1996, Science.

[24]  D. Rebholz-Schuhmann,et al.  Computer-assisted generation of a protein-interaction database for nuclear receptors. , 2003, Molecular endocrinology.

[25]  James R. Knight,et al.  A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae , 2000, Nature.

[26]  S. Khorasanizadeh,et al.  Nuclear-receptor interactions on DNA-response elements. , 2001, Trends in biochemical sciences.

[27]  James R. Knight,et al.  A Protein Interaction Map of Drosophila melanogaster , 2003, Science.

[28]  Stephen Oliver,et al.  Genome-wide analysis of the context-dependence of regulatory networks , 2005, Genome Biology.

[29]  G. Eichele,et al.  International Union of Pharmacology. LX. Retinoic Acid Receptors , 2006, Pharmacological Reviews.

[30]  D. Moore,et al.  Novel receptor interaction and repression domains in the orphan receptor SHP , 1997, Molecular and cellular biology.

[31]  R. Ozawa,et al.  A comprehensive two-hybrid analysis to explore the yeast protein interactome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Gerstein,et al.  Genomic analysis of regulatory network dynamics reveals large topological changes , 2004, Nature.

[33]  Robert A Hegele,et al.  Retinoid X receptor heterodimers in the metabolic syndrome. , 2005, The New England journal of medicine.

[34]  S. Teichmann,et al.  Gene regulatory network growth by duplication , 2004, Nature Genetics.

[35]  J. Thomsen,et al.  The Orphan Nuclear Receptor SHP Inhibits Agonist-dependent Transcriptional Activity of Estrogen Receptors ERα and ERβ* , 1999, The Journal of Biological Chemistry.

[36]  E. Nimwegen.  Scaling Laws in the Functional Content of Genomes , 2003, physics/0307001.

[37]  Bruce M. Spiegelman,et al.  Biological Control through Regulated Transcriptional Coactivators , 2004, Cell.

[38]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[39]  Wen Xie,et al.  International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. , 2006, Pharmacological reviews.

[40]  Hendrik G. Stunnenberg,et al.  Retinoic Acid Receptors , 1995 .

[41]  Paramvir S. Dehal,et al.  Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate , 2005, PLoS biology.

[42]  L. Olson,et al.  Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. , 1996, Molecular endocrinology.

[43]  R. Evans,et al.  Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network , 2006, Cell.

[44]  B. Spiegelman,et al.  International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors , 2006, Pharmacological Reviews.

[45]  Janet M. Thornton,et al.  Microeconomic Principles Explain an Optimal Genome Size in Bacteria , 2004, Spanish Bioinformatics Conference.

[46]  D. Moore,et al.  Activation of the Promoter of the Orphan Receptor SHP by Orphan Receptors That Bind DNA as Monomers* , 1999, The Journal of Biological Chemistry.

[47]  Karim Benkirane,et al.  Peroxisome proliferator-activated receptors: vascular and cardiac effects in hypertension. , 2003, Hypertension.

[48]  V. Laudet,et al.  The nuclear receptor superfamily , 2003, Journal of Cell Science.

[49]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[50]  Wen Xie,et al.  International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor , 2006, Pharmacological Reviews.

[51]  Donald P. McDonnell,et al.  International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors , 2006, Pharmacological Reviews.

[52]  Á. Pascual,et al.  Nuclear hormone receptors and gene expression. , 2001, Physiological reviews.

[53]  Michael Albers,et al.  Automated Yeast Two-hybrid Screening for Nuclear Receptor-interacting Proteins*S , 2005, Molecular & Cellular Proteomics.

[54]  Katarzyna Kalita,et al.  Estrogen receptor β , 2002 .

[55]  Samuel Refetoff,et al.  International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors , 2006, Pharmacological Reviews.

[56]  V. Craig Jordan,et al.  International Union of Pharmacology. LXIV. Estrogen Receptors , 2006, Pharmacological Reviews.

[57]  A Rowe,et al.  Retinoid X receptors. , 1997, The international journal of biochemistry & cell biology.

[58]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[59]  J. Capone,et al.  The Orphan Nuclear Hormone Receptor LXR Interacts with the Peroxisome Proliferator-activated Receptor and Inhibits Peroxisome Proliferator Signaling (*) , 1996, The Journal of Biological Chemistry.

[60]  Vincent Laudet,et al.  The nuclear receptor factsbook , 2002 .

[61]  D. Lockhart,et al.  Expression monitoring by hybridization to high-density oligonucleotide arrays , 1996, Nature Biotechnology.

[62]  D. A. Baxter,et al.  Mathematical Modeling of Gene Networks , 2000, Neuron.

[63]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[64]  Y. Bergman,et al.  A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells , 1995, Molecular and cellular biology.

[65]  J. Piatigorsky,et al.  Retinoic acid X receptor in the diploblast, Tripedalia cystophora. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[66]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[67]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[68]  D. Scott,et al.  Transcription Activation by the Orphan Nuclear Receptor, Chicken Ovalbumin Upstream Promoter-Transcription Factor I (COUP-TFI) , 2000, The Journal of Biological Chemistry.

[69]  Sarah A Teichmann,et al.  Novel specificities emerge by stepwise duplication of functional modules. , 2005, Genome research.