The long-range goal of this project is to elucidate the biochemistry and regulation of hepatic cytochrome P450 (CYP) enzymes that oxidatively metabolize steroid hormones, cholesterol and other endogenous lipophilic compounds, using the rat as a model system. The proposed project period focused on the endocrine control of sex-specific steroid hydroxylase P450 enzymes, with special emphasis on the cellular and molecular mechanism(s) by which pituitary growth hormone (GH) and its sex- dependent ultradian secretory pattern differentially regulate the expression of male-specific and female-specific steroid hydroxylase P450s in rat liver. The male-specific testosterone 2alpha/16alpha- hydroxylase CYP2C11 and the female-specific steroid sulfate 15beta- hydroxylase CYP2C12 will be studied as prototypic examples of sexually dimorphic, GH pattern-regulated liver P450 genes. Studies carried out during the last project period led to the important discovery that the signal transducer and activator of transcription STAT5b is selectively activated by the pulsatile GH pattern associated with adult male pats, and is obligatory for establishing global male patterns of liver gene expression and whole body growth rates. The major objectives of the proposed project are: (1) to further elucidate the central role of STAT5b in GH pulse regulation of male-specific liver gene expression; (2) to fully characterize the intracellular events and signaling pathways that govern the repeated activation and deactivation of STAT5b by plasma GH pulses (STAT5b cycle); (3) to elucidate the mechanisms through which GH pulse-activated STAT5b signals to the nucleus to activate CYP2C11 transcription; and (4) to identify the mechanisms through which continuous GH regulates CYP2C12 expression, including a determination of the role of the female-expressed, GH-regulated nuclear factor, GHNF in this process. These studies will provide a basic understanding, at the cellular and molecular level, of some of the key mechanisms whereby GH and its sexually dimorphic plasma profiles regulate the expression of an important family of enzymes that controls metabolic processes having a major impact on liver physiology and human health, including steroid hormone metabolism, cholesterol degradation, 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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Physical Biochemistry Study Section (PB)
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Pawlyk, Aaron
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Boston University
Schools of Arts and Sciences
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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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