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Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event
Oshida, K., N. Vasani, D. Waxman, AND C. Corton. Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event. PLoS ONE . Public Library of Science, San Francisco, CA, 11(3):NA, (2016).
A number of agencies that regulate chemicals have initiated programs to define the universe of AOPs affected by chemical exposure. These efforts are to place data from high throughput screens (e.g., EPA ToxCast screening program) iinto the context of AOP key events. The computational strategy described in this paper, i .e., using the Running Fisher's test to find biosets with similarity to transcription factor signatures will be useful in future screens to characterize chemicals, diets, infections, etc. that impact key events in AOPs and in building cumulative risk models including those that predict liver cancer and steatosis.
Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption ofthe GH hypothalamo-pituitary-liver axis controlling STAT5b activation can lead to metabolic dysregulation, steatosis, and liver cancer. Computational approaches were developed to identify factors that disrupt STAT5b function in a mouse liver gene expression compendium. A signature of 146 STAT5b-dependent genes was derived using comparisons between wild-type male and wild-type female mice and between STAT5b-null and wild-type mice. Positive and negative correlations between the STAT5b signature and a test set comprised of expression datasets (biosets) with known effects on STAT5b function were evaluated using a rank-based test (the Running Fisher's algorithm). Using a similarity p-value10•4, the test achieved a balanced accuracy of 99% and 97% for detection of STAT5b activation or STAT5b suppression, respectively. The STAT5b signature was then used to identify factors that activate (masculinize) or suppress (feminize) STAT5b function in an annotated mouse liver and primary hepatocyte gene expression compendium of -1 ,850 datasets. Disruption of GH-regulated STAT5b is a common phenomenon in liver in vivo, with 5% and 29% of the male datasets, and 11% and 13% of the female datasets, resulting in masculinization or feminization, respectively. As expected, masculinization occurred at puberty and feminization occurred during aging and in mutant mice with defects in GH signaling. A total of 70 genes were identified that have effects on STAT5b in genetic models in which the gene was inactivated or overexpressed. Other factors that affected STAT5b function were shown to include fasting, caloric restriction and infections.Together, these findings identify diverse factors that perturb the hypothala!'flo-pituitary-liver GH axis and disrupt GH-dependent STAT5b activation in mouse liver.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION