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 #
5R01DK033765-29
Application #
8209211
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
2012-02-01
Budget End
2013-01-31
Support Year
29
Fiscal Year
2012
Total Cost
$462,982
Indirect Cost
$178,070
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
Zhang, Yijing; Laz, Ekaterina V; Waxman, David J (2012) Dynamic, sex-differential STAT5 and BCL6 binding to sex-biased, growth hormone-regulated genes in adult mouse liver. Mol Cell Biol 32:880-96
Zhang, Yijing; Klein, Kathrin; Sugathan, Aarathi et al. (2011) Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One 6:e23506
Wauthier, Valerie; Sugathan, Aarathi; Meyer, Rosana D et al. (2010) Intrinsic sex differences in the early growth hormone responsiveness of sex-specific genes in mouse liver. Mol Endocrinol 24:667-78
Ling, Guoyu; Sugathan, Aarathi; Mazor, Tali et al. (2010) Unbiased, genome-wide in vivo mapping of transcriptional regulatory elements reveals sex differences in chromatin structure associated with sex-specific liver gene expression. Mol Cell Biol 30:5531-44
Laz, Ekaterina V; Sugathan, Aarathi; Waxman, David J (2009) Dynamic in vivo binding of STAT5 to growth hormone-regulated genes in intact rat liver. Sex-specific binding at low- but not high-affinity STAT5 sites. Mol Endocrinol 23:1242-54
Meyer, Rosana D; Laz, Ekaterina V; Su, Ting et al. (2009) Male-specific hepatic Bcl6: growth hormone-induced block of transcription elongation in females and binding to target genes inversely coordinated with STAT5. Mol Endocrinol 23:1914-26
Waxman, David J; Holloway, Minita G (2009) Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76:215-28

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