Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion.
Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well-characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and β-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis.
Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, 4057 Basel, Switzerland, Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, 72074 Tübingen, Germany, Department of Pharmacology and Toxicology, Michigan State University, MI 48824, USA and Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland.
Raphaëlle
R
Luisier
Elif B
EB
Unterberger
Jay I
JI
Goodman
Michael
M
Schwarz
Jonathan
J
Moggs
Rémi
R
Terranova
Erik
E
van Nimwegen
D000818:Animals; D001665:Binding Sites; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D000090702:Constitutive Androstane Receptor; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D059372:Nucleotide Motifs; D010634:Phenobarbital / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051176:beta Catenin; D010634:Phenobarbital