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: 10164773
• 负责人: DAVID J WAXMAN
• 金额: $ 49.37万
• 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/10164773
• 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; 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. 项目总结/摘要 肝脏转录组的性别差异在小鼠和人类中普遍存在，并且很大程度上受到以下因素的调节： 生长激素（GH）。该项目的长期目标是阐明这些性别差异，以更好地理解 受 GH 影响的许多临床相关性别差异的机制基础；这些包括性- 肝脏药物和类固醇代谢以及脂质代谢特征以及发生率和严重程度的差异 肝脏病理学，例如非酒精性脂肪肝病 (NAFLD) 和与肝病相关的肝纤维化 肝细胞癌的发展。我们最近对小鼠模型的研究表明，GH 通过以下方式发挥作用： 垂体分泌的性别特异性时间模式——男性呈搏动性，女性持续性——并通过 GH- 刺激肝脏 STAT5 的激活，建立性别差异的表观基因组环境，使性别 GH 在肝脏中的特殊作用。我们确定了数千个标记为假定增强子的基因组区域 具有针对 STAT5 和其他 GH 调节的重要肝脏转录因子的性别偏向结合位点；而我们 显示组蛋白 H3 赖氨酸 27 三甲基标记 (H3K27me3) 的 Ezh1/Ezh2 的性别特异性沉积是必需的 专门用于抑制男性肝脏中许多偏向女性的基因。此外，超过 200 种性别特异性 GH- 发现了受调控且核富集的长非编码 RNA (lncRNA)，并且是强有力的候选者 H3K27me3 和其他染色质标记在性别特异性基因上的性别差异沉积的调节 它们的增强子是通过对一大组多样性远交小鼠肝脏的分析来鉴定的。本项目构建 基于这些进展来阐明转录和表观遗传调控的基本机制 GH 的性别偏向基因表达对正常肝功能至关重要。拟议的工作有两个主要目标： 1) 发现支持与性别偏见性肝病相关的性别偏见基因转录的关键特征 通过识别功能活跃的性别偏见增强子，这些增强子包含脂肪的大多数遗传风险因素 肝脏疾病，并阐明其在染色质环结构域和亚结构域内的组织及其 与性别偏见基因启动子的相互作用； 2) 发现性别特异性、GH 调节的 lncRNA 在 在性别偏向的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 肝脏基因转录的性别差异，然后阐明它们对 GH- 保护作用的贡献 激活 STAT5 来对抗诱导非酒精性脂肪肝疾病和其他肝脏病变的肝脏应激。 总之，这项工作将确定 GH 及其性别依赖性血浆模式的关键机制特征， 调节数百个基因的性别偏向表达，这些基因控制肝脏代谢过程，其主要作用是 对人类健康和肝脏疾病的影响，并可能将分子特征与病理生理结果联系起来。这 所获得的结果将通过改变 GH 作用的机制焦点对该领域的研究产生重大影响 从相关性和推断函数到因果关系。这些研究也将作为脉动的范例 其他内分泌因子通过复杂的表观遗传机制发挥激素作用。