ResponseNet2.0: revealing signaling and regulatory pathways connecting your proteins and genes—now with human data

Genome sequencing and transcriptomic profiling are two widely used approaches for the identification of human disease pathways. However, each approach typically provides a limited view of disease pathways: Genome sequencing can identify disease-related mutations but rarely reveals their mode-of-action, while transcriptomic assays do not reveal the series of events that lead to the transcriptomic change. ResponseNet is an integrative network-optimization approach that we developed to fill these gaps by highlighting major signaling and regulatory molecular interaction paths that connect disease-related mutations and genes. The ResponseNet web-server provides a user-friendly interface to ResponseNet. Specifically, users can upload weighted lists of proteins and genes and obtain a sparse, weighted, molecular interaction subnetwork connecting them, that is biased toward regulatory and signaling pathways. ResponseNet2.0 enhances the functionality of the ResponseNet web-server in two important ways. First, it supports analysis of human data by offering a human interactome composed of proteins, genes and micro-RNAs. Second, it offers a new informative view of the output, including a randomization analysis, to help users assess the biological relevance of the output subnetwork. ResponseNet2.0 is available at http://netbio.bgu.ac.il/respnet .

[1]  Ming Lu,et al.  TransmiR: a transcription factor–microRNA regulation database , 2009, Nucleic Acids Res..

[2]  T. Ideker,et al.  Systematic interpretation of genetic interactions using protein networks , 2005, Nature Biotechnology.

[3]  Adam J. Smith,et al.  The Database of Interacting Proteins: 2004 update , 2004, Nucleic Acids Res..

[4]  Gary D Bader,et al.  International network of cancer genome projects , 2010, Nature.

[5]  K. Doheny,et al.  Genomewide association study for susceptibility genes contributing to familial Parkinson disease , 2009, Human Genetics.

[6]  A. Barabasi,et al.  Network medicine : a network-based approach to human disease , 2010 .

[7]  R. Sharan,et al.  Network-based prediction of protein function , 2007, Molecular systems biology.

[8]  Ernest Fraenkel,et al.  SteinerNet: a web server for integrating ‘omic’ data to discover hidden components of response pathways , 2012, Nucleic Acids Res..

[9]  Hongyu Zhao,et al.  COSINE: COndition-SpecIfic sub-NEtwork identification using a global optimization method , 2011, Bioinform..

[10]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[11]  Christie S. Chang,et al.  The BioGRID interaction database: 2013 update , 2012, Nucleic Acids Res..

[12]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[13]  Nectarios Koziris,et al.  TarBase 6.0: capturing the exponential growth of miRNA targets with experimental support , 2011, Nucleic Acids Res..

[14]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[15]  Damian Szklarczyk,et al.  STITCH 3: zooming in on protein–chemical interactions , 2011, Nucleic Acids Res..

[16]  Gary D. Bader,et al.  Cytoscape Web: an interactive web-based network browser , 2010, Bioinform..

[17]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[18]  Ron Shamir,et al.  SPIKE: a database of highly curated human signaling pathways , 2010, Nucleic Acids Res..

[19]  Maria Victoria Schneider,et al.  MINT: a Molecular INTeraction database. , 2002, FEBS letters.

[20]  D. Karger,et al.  Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity , 2009, Nature Genetics.

[21]  K. Gunsalus,et al.  Network modeling links breast cancer susceptibility and centrosome dysfunction. , 2007, Nature genetics.

[22]  L. Braathen,et al.  Regulation of the melanoma cell adhesion molecule gene in melanoma: modulation of mRNA synthesis by cyclic adenosine monophosphate, phorbol ester, and stem cell fFactor/c-kKit signaling. , 1999, The Journal of investigative dermatology.

[23]  J. Mendell,et al.  MicroRNAs in Stress Signaling and Human Disease , 2012, Cell.

[24]  Kara Dolinski,et al.  The BioGRID Interaction Database: 2011 update , 2010, Nucleic Acids Res..

[25]  Ernest Fraenkel,et al.  Swimming upstream: identifying proteomic signals that drive transcriptional changes using the interactome and multiple "-omics" datasets. , 2012, Methods in cell biology.

[26]  B. Schwikowski,et al.  A network of protein–protein interactions in yeast , 2000, Nature Biotechnology.

[27]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[28]  S. Friend,et al.  A network view of disease and compound screening , 2009, Nature Reviews Drug Discovery.

[29]  Tongbin Li,et al.  miRecords: an integrated resource for microRNA–target interactions , 2008, Nucleic Acids Res..

[30]  Ernest Fraenkel,et al.  ResponseNet: revealing signaling and regulatory networks linking genetic and transcriptomic screening data , 2011, Nucleic Acids Res..

[31]  Gary D Bader,et al.  PSICQUIC and PSISCORE: accessing and scoring molecular interactions , 2011, Nature Methods.

[32]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[33]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[34]  Livia Perfetto,et al.  MINT, the molecular interaction database: 2012 update , 2011, Nucleic Acids Res..

[35]  R. Sharan,et al.  Protein networks in disease. , 2008, Genome research.

[36]  Matthew A. Hibbs,et al.  Exploring the human genome with functional maps. , 2009, Genome research.

[37]  George N. Papadimitriou,et al.  Genetics of Late-Onset Alzheimer's Disease: Update from the Alzgene Database and Analysis of Shared Pathways , 2011, International journal of Alzheimer's disease.

[38]  Gabriela Kalna,et al.  Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase , 2011, Nature.

[39]  N. Hacohen,et al.  A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection , 2009, Cell.