Epigenetic Regulation of Mitochondrial Homeostasis and Energy Metabolism

线粒体稳态和能量代谢的表观遗传调控

基本信息

批准号：
10735059
负责人：
Qin Yang
金额：
$ 49.15万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2019-09-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735059
关键词：
Adipose tissue Antisense Oligonucleotides Binding Sites Cysteine Data Deacetylase Deacetylation Development Disease Resistance Energy Metabolism Enhancers Epigenetic Process Fatty Liver Gene Expression Genes Genomic DNA Gluconeogenesis Glucose Glucose Clamp HDAC1 gene Hepatic Hepatocyte Heterochromatin Histone Acetylation Histone Deacetylase Histones Homeostasis Human Hyperglycemia Hyperinsulinism Insulin Insulin Resistance KDM1A gene Knockout Mice Knowledge Liver Liver diseases Maps Mediating Metabolic Metabolic dysfunction Methylation Mitochondria Modification Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Translocation Obese Mice Play Protein Secretion Proteins RE1-silencing transcription factor Role Technology Up-Regulation adult obesity demethylation epigenetic regulation fatty liver disease glucose metabolism glucose production glucose tolerance glucose uptake histone methylation histone modification improved inhibitor insulin sensitivity insulin tolerance knock-down lipid metabolism non-alcoholic fatty liver non-alcoholic fatty liver disease novel programs promoter recruit tool transcription factor transcriptome sequencing unhealthy lifestyle

项目摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) contributes strongly to the development of insulin resistance, and the two mutually regulate each other in type 2 diabetes. In the liver of NAFLD and insulin resistance, hundreds to thousands of genes are either upregulated or downregulated. Epigenetic modifications such as histone methylation and acetylation modulate homochromatin or heterochromatin states to enhance or suppress gene expression in a context-dependent manner. However, significant knowledge gaps exist in mapping the epigenetic landscape and identifying the major epigenetic factors regulating the development of NAFLD and insulin resistance. In the current proposal, we take advantage of the newly developed CUT&TAG technology and create an epigenetic landscape of histone modifications, including H3K4me1 (poised marker), H3K4me2, and H3K27ac (active marker), and H3K9me2 (suppressive marker) in the liver of mouse and human NAFLD. A comprehensive analysis of the histone modification landscape identifies RE1 Silencing Transcription Factor (REST) as an epigenetic modulator that coordinates the activity of these histone markers. REST recruits histone deacetylases (HDAC1&2), which deacetylate H3K27ac, and lysine-specific demethylase 1 (LSD1), which demethylates H3K4me1 and H3K9me2, to regulate gene expression. Our preliminary data show that nuclear REST protein levels are increased in the liver of mouse and human NAFLD. Insulin and glucose treatment of cultured hepatocytes mimicking insulin resistance drives REST nuclear translocation. Knocking down REST using REST antisense oligonucleotides (ASO) in the liver of adult obese mice (REST-LKD) alleviates fatty liver and improves glucose and insulin tolerance. Hyperinsulinemic-euglycemic clamp studies show that REST knockdown in the liver increases glucose uptake in adipose tissue and muscle, indicating crosstalk between the liver and adipose tissue/muscle. These data show that hepatic REST is activated in insulin resistance, and the activated REST promotes the development of NAFLD and insulin resistance, forming a vicious cycle. Our central hypothesis is that REST is the key epigenetic factor orchestrating histone methylation and acetylation to regulate lipid and glucose metabolism in NAFLD and insulin resistance. We propose three aims to investigate what causes REST activation in NAFLD and insulin resistance, why the activated REST promotes NAFLD and insulin resistance, and how the activated REST induces systemic insulin resistance. Aim 1: To determine the mechanisms for the increased REST activity in the liver of NAFLD. Aim 2: To elucidate the mechanisms by which hepatic REST regulates lipid and glucose metabolism. Aim 3: To investigate the mechanisms for improved systemic insulin sensitivity in REST-LKD mice. Successful execution of the proposal will fill the knowledge gap by mapping the epigenetic landscape and identifying REST as a key epigenetic factor that reprograms metabolic gene profiles in NAFLD and insulin resistance.

项目摘要非酒精性脂肪肝病（NAFLD）对胰岛素抵抗的发展有很大贡献，并且两个在2型糖尿病中相互调节。在NAFLD和胰岛素抵抗的肝脏中，数百个成千上万的基因被上调或下调。表观遗传修饰，例如组蛋白甲基化和乙酰化调节同染色质或异染色质状态，以增强或抑制基因以上下文依赖的方式表达。但是，在映射表观遗传学时存在明显的知识差距景观并确定调节NAFLD和胰岛素发展的主要表观遗传因素反抗。在当前的建议中，我们利用新开发的剪切和标签技术并创建组蛋白修饰的表观遗传景观，包括H3K4ME1（固定标记），H3K4ME2和H3K27AC （活性标记）和小鼠和人NAFLD肝脏中的H3K9me2（抑制标记）。全面组蛋白修饰景观的分析将RE1识别为沉默转录因子（REST）作为一种表观遗传调节剂可以协调这些组蛋白标记的活性。 REST募集组蛋白脱乙酰基酶（HDAC1和2），脱乙酰酸H3K27AC和赖氨酸特异性脱甲基酶1（LSD1），脱甲基甲酯 H3K4ME1和H3K9ME2，以调节基因表达。我们的初步数据表明核休息蛋白小鼠和人NAFLD的肝脏中的水平升高。培养的胰岛素和葡萄糖处理模仿胰岛素耐药性的肝细胞驱动静止的核易位。用休息击倒休息成年肥胖小鼠肝脏中的反义寡核苷酸（ASO）（REST-LKD）减轻脂肪肝并改善葡萄糖和胰岛素耐受性。高胰岛素血糖夹夹研究表明，肝脏增加脂肪组织和肌肉中的葡萄糖摄取，表明肝脏和脂肪之间的串扰组织/肌肉。这些数据表明，肝休息在胰岛素抵抗中被激活，并且激活的休息促进NAFLD和胰岛素抵抗的发展，形成恶性循环。我们的中心假设是静止是整理组蛋白甲基化和乙酰化的关键表观遗传因子，以调节脂质和 NAFLD和胰岛素抵抗中的葡萄糖代谢。我们提出三个目标，以调查原因是什么原因 NAFLD和胰岛素抵抗激活，为什么激活的静止促进NAFLD和胰岛素耐药性，以及激活的静息如何诱导全身性胰岛素抵抗。目标1：确定机制 NAFLD肝脏中的休息活性增加。目标2：阐明肝休息的机制调节脂质和葡萄糖代谢。目标3：研究改善全身胰岛素的机制 REST-LKD小鼠的敏感性。提案的成功执行将通过映射来填补知识差距表观遗传景观并将休息识别为重编程代谢基因谱的关键表观遗传因素在NAFLD和胰岛素抵抗中。