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Information-dependent Enrichment Analysis Reveals Time-dependent Transcriptional Regulation of the Estrogen Pathway of Toxicity

ABSTRACT: The twenty-first century vision for toxicology involves a transition away from high-dose animal studies to in vitro and computational models (NRC 2007). This transition requires mapping pathways of toxicity by understanding how in vitro systems respond to chemical perturbation. Uncovering transcription factors/signaling networks responsible for gene expression patterns are essential for defining pathways of toxicity, and ultimately, for determining the chemical modes of action through which a toxicant acts. Traditionally transcription factor identification is achieved via chromatin immunoprecipitation studies and summarized by calculating which transcription factors are statistically associated with up- and downregulated genes. These lists are commonly determined via statistical or fold-change cutoffs, a procedure that is sensitive to statistical power and may not be as useful for determining transcription factor associations. To move away from an arbitrary statistical or fold-change based cutoffs we developed, in the context of the Mapping the Human Toxome project, an enrichment paradigm called Information Dependent Enrichment Analysis (IDEA) to guide identification of the transcription factor network. We used a test case of activation in MCF‑7 cells by 17β estradiol (E2). Using this new approach, we established a time course for transcriptional and functional responses to E2. ERα and ERβ were associated with short-term transcriptional changes in response to E2. Sustained exposure led to recruitment of additional transcription factors and alteration of cell-cycle machinery. TFAP2C and SOX2 were the transcription factors most highly correlated with dose. E2F7, E2F1 and Foxm1, which are involved in cell proliferation, were enriched only at 24h. IDEA should be useful for identifying candidate pathways of toxicity. IDEA outperforms Gene-set Enrichment Analysis (GSEA) and provides similar results to Weighted Gene Correlation Network Analysis, a platform that helps to identify genes not annotated to pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84981 | GEO | 2017/06/05

SECONDARY ACCESSION(S): PRJNA335817

REPOSITORIES: GEO

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Project description:4-Methylimidazole (4-MEI) increased incidence of lung tumors in 2-year studies in both female and male mice. We evaluated changes in gene expression in B6C3F1 mice exposed to 4-MeI for 2, 5 or 28 days using RNA-seq methods and evaluated possible molecular initiating events (MIEs) and modes-of-action (MoAs) for 4-MeI in both a target tissue for tumors (lungs) and a non-target tissue (liver). Although the magnitude of changes in differential expression was small for any one gene, there were relatively large numbers of differentially expressed genes (DEGs) at 2-days in both tissues followed by a decreasing number of DEGs at the two longer exposures. Pathway enrichment of DEGs was determined either by using specific selection criteria based on absolute value of fold-change expression (|FC|) and a false discovery rate (FDR) or with IDEA (Information Dependent Enrichment Analysis). IDEA ranks all genes in order of fold induction, both for upregulated and downregulated genes, and iteratively calculates enrichment for gene lists of different sizes. Enrichment determines whether the DEGs fall into specific biological pathways as defined by standard gene/protein ontologies, e.g. Reactome or MetaCore (GeneGO). While there were significant differences in gene expression in lungs for male and female at 2-days. There also several consistent changes for the sexes, including coordinated regulation of circadian clock genes at 2-days, downregulation of mitochondrial functions at later times, and various effects on G-protein coupled receptor (GPCR) signaling pathways. In liver, in both genders, there was upregulation of mitotic pathways at early times and downregulation of various metabolic pathways and CYPs at later times. Based on (1) structural similarities with histamine, (2) short-term CNS and testicular toxicity, (3) changes in arachidonic metabolism pathways, (4) rapid accommodation to tissue response over several days and (5) alterations in GPCR pathways, we hypothesize that the MIE for 4-MeI likely involves changes in histaminergic GPCR function. Some suggestions are provided for specific short-term studies to follow up on this hypothesis.

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Information-dependent Enrichment Analysis Reveals Time-dependent Transcriptional Regulation of the Estrogen Pathway of Toxicity

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