title: Incoherent feed-forward regulatory logic underpinning glucocorticoid receptor action.
abstract: The complexity and specificity of metazoan transcription are determined by combinatorial control of the composition and activity of regulatory complexes. To investigate the basis of this specificity, we focused on the glucocorticoid receptor (GR), a single regulatory factor that integrates multiple signals to give rise to many distinct patterns of expression. We measured the expression of a set of genes, each directly GR-regulated, but by different mechanisms in two cell lines. We varied ligand (dose, chemistry, and duration of treatment), GR (expression level and functionality), and a non-GR regulatory factor that commonly interacts with GR. Our study revealed distinct expression patterns within this set of genes, but all could be modeled by an incoherent feed-forward regulatory logic. Cellular signals, operating on GR and other factors within regulatory complexes, may define and modulate the kinetics and strength of the activating or inhibitory paths of the regulatory logic. Thus, characterizing systems behavior by perturbing single or multiple signals can reveal general principles of regulation, providing an approach to the dissection and deconvolution of combinatorial control.
authors: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
authors: Sheng-Hong
authors: SH
authors: Chen
authors: Kiriko
authors: K
authors: Masuno
authors: Samantha B
authors: SB
authors: Cooper
authors: Keith R
authors: KR
authors: Yamamoto
mesh_terms: D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C491304:ANKRD1 protein, human; D005938:Glucocorticoids; D009124:Muscle Proteins; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D003907:Dexamethasone; D048031:JNK Mitogen-Activated Protein Kinases