title: Loregic: a method to characterize the cooperative logic of regulatory factors.
abstract: The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet's observed gene expression pattern across many conditions. We make Loregic available as a general-purpose tool (github.com/gersteinlab/loregic). We validate it with known yeast transcription-factor knockout experiments. Next, using human ENCODE ChIP-Seq and TCGA RNA-Seq data, we are able to demonstrate how Loregic characterizes complex circuits involving both proximally and distally regulating transcription factors (TFs) and also miRNAs. Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs. Finally, we inter-relate Loregic's gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy.
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Daifeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Koon-Kiu
authors.initials: KK
authors.lastname: Yan
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sisu
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Rozowsky
authors.affiliation: School of Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Meyerson
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America; Department of Computer Science, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
mesh_terms: D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D005809:Genes, Regulator / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics; D016015:Logistic Models; D035683:MicroRNAs / Q000235:genetics; D008957:Models, Genetic; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors