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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033765-31
Application #
8584283
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Pawlyk, Aaron
Project Start
1999-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
31
Fiscal Year
2014
Total Cost
$546,761
Indirect Cost
$212,759
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
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
Conforto, Tara L; Zhang, Yijing; Sherman, Jennifer et al. (2012) Impact of CUX2 on the female mouse liver transcriptome: activation of female-biased genes and repression of male-biased genes. Mol Cell Biol 32:4611-27
Shao, Zhen; Zhang, Yijing; Yuan, Guo-Cheng et al. (2012) MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets. Genome Biol 13:R16
Conforto, Tara L; Waxman, David J (2012) Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood. Biol Sex Differ 3:9

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