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.
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.
|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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