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

基本信息

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
项目类别：
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

项目摘要

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：该项目的长期目标是阐明这些性别差异，以便更好地理解。受 GH 影响的许多临床相关性别差异的机制基础包括性别；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我们最近在小鼠模型中的研究表明，GH 通过以下途径发挥作用。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，使性别我们鉴定了数千个基因组区域，这些区域被标记为假定的增强子。具有性别偏向的 STAT5 和其他 GH 调节的肝脏转录因子的结合位点；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女性偏向的基因此外，还有 200 多种性别特异性 GH- 基因。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通过分析该项目构建的大量多样性远交小鼠肝脏，鉴定出了它们的增强子。基于这些进展来阐明转录和表观遗传调控的基本机制 GH 确定对正常肝功能至关重要的性别偏见基因表达。这项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向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。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。其他内分泌因素的激素作用通过复杂的表观遗传机制发挥作用。