title: Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms.
abstract: Combinatorial control of gene expression is presumed to be mediated by molecular interactions between coincident transcription factors (TFs). While information on the genome-wide locations of TFs is available, the genes they regulate and whether they function combinatorially often remain open questions. Here, we developed a mechanistic, rather than statistical, modeling approach to elucidate TF control logic from gene expression data. Applying this approach to hundreds of genes in 85 datasets measuring the transcriptional responses of murine fibroblasts and macrophages to cytokines and pathogens, we found that stimulus-responsive TFs generally function sequentially in logical OR gates or singly. Logical AND gates were found between NF-κB-responsive mRNA synthesis and MAPKp38-responsive control of mRNA half-life, but not between temporally coincident TFs. Our analyses identified the functional target genes of each of the pathogen-responsive TFs and prompt a revision of the conceptual underpinnings of combinatorial control of gene expression to include sequentially acting molecular mechanisms that govern mRNA synthesis and decay.
authors.affiliation: Signaling Systems Laboratory, San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Cheng
authors.affiliation: Signaling Systems Laboratory, San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences (QCBio) and Molecular Biology Institute (MBI), University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Marcelo S
authors.initials: MS
authors.lastname: Behar
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences (QCBio) and Molecular Biology Institute (MBI), University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Gajendra W
authors.initials: GW
authors.lastname: Suryawanshi
authors.affiliation: Signaling Systems Laboratory, San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Kristyn E
authors.initials: KE
authors.lastname: Feldman
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences (QCBio) and Molecular Biology Institute (MBI), University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Signaling Systems Laboratory, San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences (QCBio) and Molecular Biology Institute (MBI), University of California, Los Angeles, Los Angeles, CA 90025, USA. Electronic address: ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D003198:Computer Simulation; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology
chemical_list: D014157:Transcription Factors
keywords: combinatorial control; gene expression; gene regulatory logic; mathematical modeling; pathogen responses