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：
10469401
负责人：
Qin Yang
金额：
$ 39.25万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469401
关键词：
Adhesions Adipocytes Adipose tissue Adult Aging Applications Grants Biology Brown Fat Cells Complement 1q Complex Cyclic AMP DNA Data Development Diabetes Mellitus Disease Energy Metabolism Enhancers Enzymes Epigenetic Process Excision Fatty Liver G-Protein-Coupled Receptors GDF15 gene Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Hepatic Hepatocyte High Fat Diet Histones Homeostasis Housekeeping KDM1A gene Knock-out Laboratories Ligands Liver Liver Mitochondria Longevity Lysine Mediating Metabolic Metabolism Methylation Mitochondria Modeling Molecular Mus Nicotinamide-Nucleotide Adenylyltransferase Nuclear Nuclear Proteins Obese Mice Obesity Organ Organelles Oxidative Phosphorylation Pathway interactions Phosphorylation Physiological Play Positioning Attribute Production Proteins Proteomics Recombinant Proteins Regulation Research Role SIRT1 gene Signal Transduction Stress System Tissues adiponectin aged epigenetic regulation feeding fibroblast growth factor 21 fly gene function glucose metabolism glucose tolerance histone demethylase histone methylation humanin improved insight knock-down member metabolic phenotype mitochondrial dysfunction non-histone protein novel obesity treatment overexpression synthetic enzyme transcription factor transcriptome sequencing

项目摘要

Mitochondria are powerhouses regulating cellular and systemic energy metabolism. Although mitochondria have their own DNA encoding 13 oxidative phosphorylation proteins, mitochondrial function is mainly regulated by more than 1,000 proteins encoded by the “mitochondrial genes” in the nuclear genome. While transcription factors have been the focus of research on mitochondrial gene regulation, major gaps exist in understanding how epigenetic factors are integrated into the transcriptional networks. Here the applicant proposes that lysine-specific demethylase-1 (LSD1) in liver serves as a novel housekeeping mechanism coordinating histone methylation and NAD+-modulated transcription factors to control mitochondrial gene expression and function and to regulate systemic energy metabolism. LSD1 catalyzes the removal of mono- and di-methylation of lysine 4 and 9 on histone 3 (H3K4/9). LSD1 also targets non-histone proteins to regulate their activity. Hepatic LSD1 was reduced in aged and obese mice. As LSD1 is essential to development, the applicant’s laboratory generated liver-specific LSD1 knockout in adult mice (LSD1-LKO). RNA-seq analysis revealed that LSD1 knockout in liver decreased approximately one-third of all known mitochondrial genes. Preliminary mechanistic studies showed that H3K9 methylation contributed to mitochondrial gene reduction. LSD1 did not directly target mitochondrial transcription factors, but rather targeted NAD+-synthetic enzyme NMNAT1 to regulate the activity of Sirt1 and Sirt7, which are positioned upstream of the mitochondrial transcription factors. Surprisingly, despite the reduced hepatic mitochondrial gene expression and function, LSD1-LKO mice showed improved metabolic phenotype including increased energy expenditure and reduced adiposity. We identified complement C1q like 4 (C1ql4), a member of adiponectin superfamily, as a potential novel mitochondrial stress-induced hepatic mitokine that regulates systemic energy expenditure. The applicant therefore hypothesizes that LSD1 modulates histone and NMNAT1 methylation to control mitochondrial gene expression and hepatic mitokine production for regulating systemic energy metabolism. Aim 1 is to determine the mechanisms for LSD1-regulated hepatic mitochondrial gene expression, focusing on 1) LSD1 demethylase activity and histone methylation; 2) NMNAT1 methylation and NAD+-mediated transcription factor activation. Aim 2 is to elucidate the mechanisms by which hepatic LSD1 regulates systemic energy metabolism. We will focus on C1ql4 and study 1) regulation of C1ql4 expression by mitochondrial stress and histone methylation; 2) effects of C1ql4 on obesity; 3) mechanism of C1ql4 action for increasing energy expenditure; 4) role of C1ql4 induction in the improved systemic energy metabolism in the LSD1-LKO mice. Overall, the proposal will provide molecular, cellular and physiological insights into the housekeeping roles of LSD1 in controlling mitochondrial gene expression and function. Furthermore, the identification of C1ql4 as a novel hepatic mitokine not only highlights the significance of mitokines in regulating systemic energy metabolism, but may also provide a novel target for obesity treatment.

线粒体是控制细胞和全身能量代谢的动力。尽管线粒体具有编码13个氧化磷酸化蛋白的DNA，但线粒体功能主要由核基因组中“线粒体基因”编码的1,000多个蛋白质调节。虽然转录因子一直是线粒体基因调节的研究重点，但在理解如何将表观遗传因子整合到转录网络中时存在主要差距。在这里，肝脏中赖氨酸特异性去甲基酶-1（LSD1）的适用提议是一种新型的家政机制协调组蛋白甲基化和NAD+调节的转录因子，以控制线粒体基因的表达和功能，并调节系统能量代谢。 LSD1催化了组蛋白3（H3K4/9）上赖氨酸4和9的单甲基化的去除。 LSD1还靶向非历史蛋白来调节其活性。在老年小鼠和肥胖的小鼠中，肝LSD1降低了。由于LSD1对于开发至关重要，因此该应用程序的实验室在成年小鼠（LSD1-LKO）中产生了肝特异性LSD1敲除。 RNA-seq分析表明，肝脏中的LSD1基因敲除大约降低了所有已知线粒体基因的三分之一。初步机械研究表明，H3K9甲基化有助于线粒体基因还原。 LSD1并非直接靶向线粒体转录因子，而是针对NAD+ - 合成酶NMNAT1来调节SIRT1和SIRT7的活性，SIRT1和SIRT7的活性位于线粒体转录因子上游。令人惊讶的是，LSD1-LKO小鼠努力努力减少的肝脏线粒体基因表达和功能，表现出改善的代谢表型，包括增加能量消耗和脂肪降低。我们确定了脂联素超家族的成员4（C1QL4）的完成C1Q，是一种潜在的新型线粒体应激诱导的肝脱脂式线粒体，可调节系统性能量消耗。因此，适当的假设是LSD1调节组蛋白和NMNAT1甲基化以控制线粒体基因的表达和肝素线虫的产生，以控制全身能量代谢。目的1是确定LSD1调节的肝线粒体基因表达的机制，重点是1）LSD1脱甲基酶活性和组蛋白甲基化； 2）NMNAT1甲基化和NAD+介导的转录因子激活。目的2是阐明肝LSD1调节系统能量代谢的机制。我们将重点关注C1QL4和研究1）通过线粒体应激和组蛋白甲基化对C1QL4表达的调节； 2）C1QL4对肥胖症的影响； 3）C1QL4动作增加能量消耗的机制； 4）C1QL4诱导在改善LSD1-LKO小鼠的全身能量代谢中的作用。总体而言，该提案将提供分子，细胞和物理见解，以对LSD1的管家在控制线粒体基因表达和功能中的管家作用。此外，将C1QL4鉴定为一种新型的肝脏有丝分裂，不仅突出了有丝分裂因子在恢复系统性能量代谢中的重要性，而且还可能为肥胖治疗提供了新的靶标。