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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Pawlyk, Aaron
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Boston University
Schools of Arts and Sciences
United States
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Matthews, Bryan J; Waxman, David J (2018) Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver. Elife 7:
Hao, Pengying; Waxman, David J (2018) Functional Roles of Sex-Biased, Growth Hormone-Regulated MicroRNAs miR-1948 and miR-802 in Young Adult Mouse Liver. Endocrinology 159:1377-1392
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) 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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