title: iRegulon: from a gene list to a gene regulatory network using large motif and track collections.
abstract: Identifying master regulators of biological processes and mapping their downstream gene networks are key challenges in systems biology. We developed a computational method, called iRegulon, to reverse-engineer the transcriptional regulatory network underlying a co-expressed gene set using cis-regulatory sequence analysis. iRegulon implements a genome-wide ranking-and-recovery approach to detect enriched transcription factor motifs and their optimal sets of direct targets. We increase the accuracy of network inference by using very large motif collections of up to ten thousand position weight matrices collected from various species, and linking these to candidate human TFs via a motif2TF procedure. We validate iRegulon on gene sets derived from ENCODE ChIP-seq data with increasing levels of noise, and we compare iRegulon with existing motif discovery methods. Next, we use iRegulon on more challenging types of gene lists, including microRNA target sets, protein-protein interaction networks, and genetic perturbation data. In particular, we over-activate p53 in breast cancer cells, followed by RNA-seq and ChIP-seq, and could identify an extensive up-regulated network controlled directly by p53. Similarly we map a repressive network with no indication of direct p53 regulation but rather an indirect effect via E2F and NFY. Finally, we generalize our computational framework to include regulatory tracks such as ChIP-seq data and show how motif and track discovery can be combined to map functional regulatory interactions among co-expressed genes. iRegulon is available as a Cytoscape plugin from http://iregulon.aertslab.org.
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Rekin's
authors: R
authors: Janky
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Annelien
authors: A
authors: Verfaillie
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Hana
authors: H
authors: Imrichová
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Bram
authors: B
authors: Van de Sande
authors: Laboratory for Molecular Cancer Biology, KU Leuven Center for Human Genetics, Leuven, Belgium; VIB Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, Leuven, Belgium.
authors: Laura
authors: L
authors: Standaert
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Valerie
authors: V
authors: Christiaens
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Gert
authors: G
authors: Hulselmans
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Koen
authors: K
authors: Herten
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Marina
authors: M
authors: Naval Sanchez
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Delphine
authors: D
authors: Potier
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Dmitry
authors: D
authors: Svetlichnyy
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Zeynep
authors: Z
authors: Kalender Atak
authors: VIB Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, Leuven, Belgium.
authors: Mark
authors: M
authors: Fiers
authors: Laboratory for Molecular Cancer Biology, KU Leuven Center for Human Genetics, Leuven, Belgium; VIB Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, Leuven, Belgium.
authors: Jean-Christophe
authors: JC
authors: Marine
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors: Stein
authors: S
authors: Aerts
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D008957:Models, Genetic; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors