Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms

Christine S. Cheng, Marcelo S. Behar, Gajendra W. Suryawanshi, Kristyn E. Feldman, Roberto Spreafico, Alexander Hoffmann
2017 Cell Systems  
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
more » ... asuring 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 NFκB-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 prompts a revision of the conceptual underpinnings of combinatorial control of gene expression to include sequentially acting molecular mechanisms that govern mRNA synthesis and decay. ‡
doi:10.1016/j.cels.2017.01.012 pmid:28237795 pmcid:PMC5434763 fatcat:g3luu3ecwrappahx2b4dfyslmu