Growth Hormone Regulation of Sex Differences in Liver Metabolism

生长激素对肝脏代谢性别差异的调节

• 批准号: 10402862
• 负责人: DAVID J WAXMAN
• 金额: $ 49.5万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402862
• 关键词: Abbreviations; Ablation; Address; Affect; Binding Sites; Biological; Biological Assay; Chromatin; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Code; Complex; Correlative Study; Deoxyribonucleases; Dependovirus; Deposition; Development; Diagnosis; Disease; Disease model; Disease susceptibility; Distal; Distant; Endocrine; Enhancers; Environment; Enzymes; Epigenetic Process; Etiology; Fatty Liver; Female; Gene Expression; Genes; Genetic Transcription; Genome; Genomic Segment; Genomics; Goals; Guide RNA; Health; Hepatic; Histone H3; Hormonal; Hormones; Human; Hypersensitivity; Incidence; Individual; Infusion procedures; Injections; Link; Lipids; Liver; Liver Fibrosis; Liver diseases; Lysine; Malignant neoplasm of liver; Metabolic; Metabolism; Molecular; Mus; Nuclear; Nucleic Acid Regulatory Sequences; Outcome; Pathology; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiology; Pituitary Gland; Pituitary Hormones; Plasma; Polycomb; Primary carcinoma of the liver cells; Proteins; Quantitative Trait Loci; RNA; Regulation; Regulatory Element; Reporter; Repression; Repressor Proteins; Research; Role; Scheme; Severities; Sex Bias; Sex Differences; Sex Differentiation; Site; Somatotropin; Stat5 protein; Steroids; Stress; Testing; Transcription Coactivator; Transcription Initiation Site; Transcriptional Regulation; Transferase; Untranslated RNA; Work; base; chromatin immunoprecipitation; chromosome conformation capture; clinically relevant; dietary; drug metabolism; endonuclease; epigenetic regulation; epigenetic silencing; epigenomics; fatty liver disease; functional outcomes; genetic risk factor; hepatotoxin; hormone regulation; in vivo; knock-down; liver function; liver metabolism; male; member; metabolic profile; mouse model; non-alcoholic fatty liver disease; prevent; promoter; protective effect; response; sex; steroid metabolism; toxicant; transcription factor; transcriptome

7. Project Summary/Abstract Sex differences in the liver transcriptome are widespread in both mice and humans and are largely regulated by growth hormone (GH). The long-term goal of this project is to elucidate these sex differences to better understand the mechanistic underpinnings of the many clinically relevant sex differences impacted by GH; these include sex- differences in hepatic drug and steroid metabolism and lipid metabolic profiles, and in the incidence and severity of liver pathologies, such as non-alcoholic fatty liver disease (NAFLD) and liver fibrosis associated with development of hepatocellular carcinoma. Our recent studies in the mouse model revealed that GH acts through its sex-specific temporal patterns of pituitary secretion – pulsatile in males and persistent in females — and via GH- stimulated activation of liver STAT5, to establish a sex-differential epigenomic environment that enables the sex- specific actions of GH in the liver. We identified several thousand genomic regions marked as putative enhancers that have sex-biased binding sites for STAT5 and other essential GH-regulated liver transcription factors; and we showed that sex-specific deposition by Ezh1/Ezh2 of histone-H3 lysine 27 trimethyl marks (H3K27me3) is required specifically for the repression of many female-biased genes in male liver. Further, more than 200 sex-specific, GH- regulated and nuclear-enriched long, non-coding RNAs (lncRNAs) were discovered, and strong candidates for regulation of the sex-differential deposition of H3K27me3 and other chromatin marks at sex-specific genes and their enhancers were identified by analysis of a large panel of Diversity Outbred mouse livers. This project builds on these advances to elucidate fundamental mechanisms that underlie the transcriptional and epigenetic regulation by GH of sex-biased gene expression essential for normal liver function. The work proposed has two major aims: 1) to discover critical features that underpin sex-biased gene transcription associated with sex-biased liver disease by identifying functionally active sex-biased enhancers, which harbor the majority of genetic risk factors for fatty liver disease, and to elucidate their organization within chromatin loop domains and subdomains, and their interactions with sex-biased gene promoters; and 2) to discover the role of sex-specific, GH-regulated lncRNAs in establishing and maintaining the sex-differentiated chromatin states at sex-biased enhancers and genes to support sex differences in liver gene transcription, and then elucidate their contributions to the protective effects of GH- activated STAT5 against hepatic stresses that induce non-alcoholic fatty liver disease and other liver pathologies. Together, this work will identify key mechanistic features that enable GH, and its sex-dependent plasma patterns, to regulate the sex-biased expression of hundreds of genes that control liver metabolic processes with a major impact on human health and liver disease, and may link molecular features to pathophysiological outcomes. The results obtained will have a high impact on research in this field by shifting the mechanistic focus of GH action from correlation and inferred function to causality. These studies will also serve as a paradigm for the pulsatile hormone action of other endocrine factors that act through complex epigenetic mechanisms.

7。项目摘要/摘要 肝转录组的性别差异在小鼠和人类中都是宽度的，很大程度上受到 成长马（GH）。该项目的长期目标是阐明这些性别差异以更好地理解 许多受GH影响的许多临床相关性别差异的机械基础；这些包括性别 - 肝药物和类固醇代谢和脂质代谢谱的差异以及事件和严重程度 肝脏病理，例如非酒精性脂肪肝病（NAFLD）和肝纤维化 肝细胞癌的发展。我们最近在鼠标模型中的研究表明，GH通过 它的性别特异性临时分泌模式 - 男性脉动和女性的持续性 - 以及通过gh- 刺激肝Stat5的激活，以建立一个性别差异的表观基因组环境，使性别 - GH在肝脏中的具体作用。我们确定了标记为推定增强剂的数千个基因组区域 具有STAT5和其他基本GH调节肝转录因子的性偏见的结合位点；还有我们 表明需要EZH1/EZH2的性别特定沉积物，需要Hisstone-H3赖氨酸27三甲基标记（H3K27ME3） 专门用于雄性肝中许多雌性偏见基因的表达。此外，超过200个性别特定的GH- 发现了受调节和核富集的长，非编码RNA（LNCRNA），并强大的候选者 在性别特异性基因和 通过分析大量多样性小鼠寿命的分析，可以确定它们的增强剂。这个项目建立 这些进步阐明了基本机制，这些机制是转录和表观遗传学调节的基础 通过性别偏见的基因表达的GH对于正常肝功能必不可少。拟议的工作有两个主要目标： 1）发现基于性别偏见的性偏置肝病的基因转录的关键特征 通过识别功能活跃的性偏向增强剂，这些增强剂具有大多数脂肪的遗传风险因素 肝病，并在染色质环域和亚域内阐明其组织及其组织 与性别偏见的基因启动子的相互作用； 2）发现性别特异性，受GH调节的lncrnas在 在性别偏向增强子和基因上建立和维持性别分化的染色质状态以支持 肝基因转录的性别差异，然后阐明其对GH-受保护作用的贡献 激活的STAT5针对肝炎应激会诱导非酒精性脂肪肝病和其他肝脏病理。 这项工作将共同确定使GH及其性别依赖性血浆模式的关键机械特征，即 调节数百个基因的性偏见表达，这些基因控制肝脏代谢过程 对人类健康和肝病的影响，并可能将分子特征与病理生理结果联系起来。这 获得的结果将通过移动GH动作的机械重点对该领域的研究产生很大的影响 从相关性和推断功能到因果关系。这些研究还将作为脉动的范例 通过复杂的表观遗传机制起作用的其他内分泌因子的骑马作用。