The long-range goal of this project is to elucidate the endocrine regulation of hepatic cytochromes P450 (Cyps) and other enzymes that metabolize steroid hormones, bile acids, carcinogens and other lipophilic substrates of medical or environmental importance, with a focus on the actions of growth hormone (GH), a pituitary polypeptide hormone. The proposed project period uses the mouse as a model system to investigate the molecular mechanisms by which GH and its sex-dependent ultradian secretory patterns regulate Cyps and many other liver-expressed genes in a sex-specific manner. The major objective of this project is to elucidate the mechanisms that underpin the dependence of sex-specific liver gene expression on STAT5b, a signal transducer and activator of transcription that is directly activated by each incoming adult male plasma GH pulse, and on HNF41, a liver-enriched transcription factor. The studies proposed will test the hypothesis that the actions of STAT5b and HNF41 on sex-specific Cyps and other GH pulse-responsive genes involve both direct and indirect mechanisms operating through a complex regulatory network. Genome-wide approaches will be used to elucidate key components and features of the overall network through the discovery of 1) novel primary targets of GH-activated STAT5b, 2) epigenetic regulatory mechanisms controlled by GH that may lead to long-term gene silencing, and 3) transcription factors that act proximal to downstream Cyp genes. Together, these studies will elucidate key features of the intracellular events that determine the complex, GH-dependent patterns of expression of hepatic Cyps, which control metabolic processes having a major impact on liver physiology and human health, including steroid hormone metabolism, cholesterol catabolism, drug biotransformation and carcinogen activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033765-27
Application #
7758711
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Pawlyk, Aaron
Project Start
1999-04-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
27
Fiscal Year
2010
Total Cost
$557,729
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Yu, Ai-Ming; Ingelman-Sundberg, Magnus; Cherrington, Nathan J et al. (2017) Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 7:241-248
Lau-Corona, Dana; Suvorov, Alexander; Waxman, David J (2017) Feminization of male mouse liver by persistent growth hormone stimulation: Activation of sex-biased transcriptional networks and dynamic changes in chromatin states. Mol Cell Biol :
Connerney, Jeannette; Lau-Corona, Dana; Rampersaud, Andy et al. (2017) Activation of Male Liver Chromatin Accessibility and STAT5-Dependent Gene Transcription by Plasma Growth Hormone Pulses. Endocrinology 158:1386-1405
Oshida, Keiyu; Waxman, David J; Corton, J Christopher (2016) Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome. PLoS One 11:e0150284
Oshida, Keiyu; Vasani, Naresh; Waxman, David J et al. (2016) Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event. PLoS One 11:e0148308
Melia, Tisha; Hao, Pengying; Yilmaz, Feyza et al. (2016) Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone. Mol Cell Biol 36:50-69
Conforto, Tara L; Steinhardt 4th, George F; Waxman, David J (2015) Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver. Mol Endocrinol 29:1286-302
Ling, Guoyu; Waxman, David J (2013) DNase I digestion of isolated nulcei for genome-wide mapping of DNase hypersensitivity sites in chromatin. Methods Mol Biol 977:21-33
Sugathan, Aarathi; Waxman, David J (2013) Genome-wide analysis of chromatin states reveals distinct mechanisms of sex-dependent gene regulation in male and female mouse liver. Mol Cell Biol 33:3594-610
Ling, Guoyu; Waxman, David J (2013) Isolation of nuclei for use in genome-wide DNase hypersensitivity assays to probe chromatin structure. Methods Mol Biol 977:13-9

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