Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion

作     者：Luisier, Raphaelle Unterberger, Elif B. Goodman, Jay I. Schwarz, Michael Moggs, Jonathan Terranova, Remi van Nimwegen, Erik 

作者机构：Novartis Inst Biomed Res CH-4057 Basel Switzerland Univ Tubingen Inst Expt & Clin Pharmacol & Toxicol Dept Toxicol D-72074 Tubingen Germany Michigan State Univ Dept Pharmacol & Toxicol E Lansing MI 48824 USA Univ Basel Biozentrum CH-4056 Basel Switzerland Swiss Inst Bioinformat CH-4056 Basel Switzerland 

出 版 物：《NUCLEIC ACIDS RESEARCH》 (Nucleic Acids Res.)

年 卷 期：2014年第42卷第7期

页      面：4180-4195页

核心收录：

学科分类：0710[理学-生物学] 08[工学] 09[农学] 0901[农学-作物学] 0836[工学-生物工程] 090102[农学-作物遗传育种] 

基　　金：Innovative Medicine Initiative Joint Undertaking (IMI JU) Novartis Swiss Systems Biology Initiative SystemsX.ch within the network "Cellplasticity" University of Basel 

主　　题：constitutive androstane receptor Automatic format recognition Regulator Genes Crucial components Neoplastic Cell Transformation beta Catenin Tumor Promotion Transcription Factors Computational modeling 

摘      要：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 beta-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.