Sex differences are widespread in both mouse and human liver, and are associated with clinically relevant sex differences in hepatic drug and steroid metabolism, lipid metabolic profiles, the incidence of liver cancer, and cardiovascular disease risk. This application focuses on the genomic and epigenomic actions of growth hormone (GH), a pituitary polypeptide hormone and major regulator of liver metabolic functions, in particular those that show sex differences. The studies proposed test the hypothesis that GH regulates the chromatin states of sex-specific genes, and thereby establishes an epigenomic environment that facilitates the sex- specific actions of GH in the liver. The mouse model will be used to investigate the mechanisms by which GH, via its sex-specific temporal patterns of pituitary gland secretion (pulsatile in males vs. near continuous in females), activates transcriptional pathways and epigenetic events that regulate hundreds of liver-expressed genes in a sex-specific manner. Major progress during the last project period included the discovery of key GH-dependent transcriptional activators and repressors that interact on a genome-wide level and regulate sex differences in the liver, the development of global maps of accessible chromatin regions (DNase hypersensitivity) and epigenetic signatures (chromatin marks) that identify several hundred sex-specific regulatory elements, and the discovery of novel sex-specific long, intergenic non-coding RNA genes that are GH-regulated and may determine sex-specific chromatin states. These findings provide a unique opportunity to move the field forward by elucidating genome-wide, and at the epigenetic level, the fundamental biological mechanisms that underlie the complex regulation of sex differences in the liver by pituitary GH secretory patterns. This will be accomplished through the discovery of: 1) chromatin states and their associated transcription factor motifs that characterize distinct subsets of sex-specific genes;2) distal regulatory elements and their interactions with sex-specific target genes;and 3) the role of sex-specific, GH-regulated long, intergenic non-coding RNA genes in establishing and maintaining the sex-differentiated chromatin states that facilitate sex differential liver gene transcription. Together, these studies will identify key mechanistic features that determine the complex, GH-regulated and sex-biased expression of genes that control liver metabolic processes with a major impact on human health. The results obtained are expected to have a high impact, shifting the mechanistic focus of studies on GH action to the epigenome, and will serve as a paradigm for other endocrine factors that alter the epigenome in complex ways.

Public Health Relevance

This project investigates how growth hormone regulates liver enzymes and liver function in ways that differ between males and females. These studies have important implications for the influence of sex and hormone status on the processing in the liver of cholesterol, hormones, drugs, cancer-causing chemicals and other substances of medical and environmental importance.

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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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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