权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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性肝病（NAFLD）强烈促进胰岛素抵抗的发展，在2型糖尿病中两者相互调节。在NAFLD和胰岛素抵抗的肝脏中，成千上万的基因被上调或下调。表观遗传修饰，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表达以上下文相关的方式表达。然而，在绘制表观遗传图谱方面存在着重大的知识缺口。景观和确定调节NAFLD和胰岛素发展的主要表观遗传因素阻力在当前的提案中，我们利用新开发的CUT&TAG技术，组蛋白修饰的表观遗传景观，包括H3 K4 me 1（平衡标记），H3 K4 me 2和H3 K27 ac 在小鼠和人NAFLD的肝脏中，H3 K9 me 2（活性标志物）和H3 K9 me 2（抑制标志物）的表达。全面对组蛋白修饰景观的分析将RE 1沉默转录因子（REST）鉴定为一种表观遗传调节剂协调这些组蛋白标记物的活性。REST募集组蛋白去乙酰化酶（HDAC 1&2），其使H3 K27 ac脱乙酰;和赖氨酸特异性脱甲基酶1（LSD 1），其使H3 K27 ac脱甲基。 H3 K4 me 1和H3 K9 me 2，以调节基因表达。我们的初步数据显示，在小鼠和人NAFLD的肝脏中，胰岛素和葡萄糖处理培养的模拟胰岛素抵抗的肝细胞驱动REST核转位。使用REST来击倒REST 反义寡核苷酸（阿索）在成年肥胖小鼠（REST-LKD）肝脏中的表达可减轻脂肪肝，葡萄糖和胰岛素耐受性。高胰岛素-正葡萄糖钳夹研究表明，肝脏增加脂肪组织和肌肉中的葡萄糖摄取，表明肝脏和脂肪组织之间的串扰。组织/肌肉。这些数据表明，肝脏REST在胰岛素抵抗中被激活，并且激活的REST 促进NAFLD和胰岛素抵抗的发展，形成恶性循环。我们的核心假设是 REST是协调组蛋白甲基化和乙酰化以调节脂质的关键表观遗传因子， NAFLD中的葡萄糖代谢和胰岛素抵抗。我们提出了三个目标来调查是什么导致了REST 激活NAFLD和胰岛素抵抗，为什么激活的REST会促进NAFLD和胰岛素抵抗，以及激活的REST如何诱导全身性胰岛素抵抗。目标1：确定 NAFLD肝脏中的REST活性增加。目的2：阐明肝脏REST 调节脂质和葡萄糖代谢。目的3：探讨改善全身胰岛素水平的机制在REST-LKD小鼠中的敏感性。成功执行该提案将通过绘制表观遗传景观，并将REST确定为重新编程代谢基因谱的关键表观遗传因素 NAFLD和胰岛素抵抗。