Role of methylation-dependent pathways in aging and stress

甲基化依赖性途径在衰老和压力中的作用

基本信息

批准号：
10172812
负责人：
Amy Karol Walker
金额：
$ 40.52万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172812
关键词：
Address Affect Aging Animals Attenuated Biological Assay Caenorhabditis elegans Calories Cell physiology Cells Chromatin Cystic Fibrosis Defect Diet Diet Modification Disease Disease model Drug Metabolic Detoxication Epigenetic Process Escherichia coli Failure Fatty Liver Fatty acid glycerol esters Folic Acid Gene Activation Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Guanosine Triphosphate Phosphohydrolases HMGB1 Protein Histones Immune Immune response Immune signaling Immune system Immunity Immunologic Markers Laboratories Lecithin Link Lipids Liver diseases Mediating Membrane Metabolic Metabolism Methylation Methyltransferase Mitogen-Activated Protein Kinases Modeling Molecular Mutation Natural Immunity Nutrient Pathogenicity Pathway interactions Phenotype Phospholipids Phosphorylation Physiological Physiology Process Production Pseudomonas Pseudomonas aeruginosa RNA interference screen Regulation Reporter Role S-Adenosylmethionine SRE-1 binding protein Signal Pathway Signal Transduction Sphingomyelins Stimulus Stress System Techniques Transcriptional Regulation Up-Regulation Vitamin B 12 Walkers Work activating transcription factor biological adaptation to stress chromatin modification deep sequencing dietary histone methylation histone methyltransferase histone modification immune activation innate immune function insight lipidomics p38 Mitogen Activated Protein Kinase pathogen response transcriptome sequencing whole genome

项目摘要

Diet and metabolism can affect how our bodies work in many ways, not just by turning excess calories into fat. Some metabolites act as signals or can be used to modify how genes are expressed, which can link diet to how our cells function and their capacity to respond to stress. We propose to study how one metabolite, s-adenosylmethionine (SAM), can both activate markers of immunity and limit how cells can change gene expression patterns in response to pathogens or other stress. These seemingly paradoxical functions occur because SAM can be used for different cellular needs. SAM can be used to make the phospholipid phosphatidylcholine (PC) and when PC is limited by the diet or needed for extra membrane production, much of the SAM is used for this biosynthetic process. However, SAM is also needed for modification of histones. Using C. elegans, we found that low SAM acted through low PC to activate markers of innate immunity on the standard laboratory diet. However, these same animals could not survive a bacterial challenge because they couldn't methylate histones priming gene activation and turn up pathogen responsive genes to sufficient levels. Thus, different contexts can change the phenotypes of low SAM, as cells need to prioritize utilization of this metabolite. Our proposal addresses several key questions. First, it is not known how the low SAM and PC signal activation of the immune system. Second, it is not understood how global chromatin modification under stress might change in low SAM and third, we don't yet understand how physiological regulators of low SAM might affect either of these phenotypes. Our C. elegans system is an excellent model for dissecting these mechanisms. We will combine genetic and molecular techniques (including whole genome assays for chromatin modification) with dietary modification to determine how SAM is linked to these phenotypes. We have used screens for SAM and PC-dependent modifiers of immunity to identify additional regulatory components and propose to determine how these candidates may be connected to immune activation. Furthermore, we have determined that multiple types of stress-induced gene expression depend on SAM and will use this system to ask how SAM and the histone methyltransferases utilizing it control transcription during stress. Although low SAM can cause phenotypes with very distinct molecular mechanisms, such as lipid-dependent activation of a MAP kinase in the immune response and modification of histones in transcriptional regulation, it is important to study these processes together. SAM depletion due to diet may impact either or both of these mechanisms, changing how our cells can respond to stress.

饮食和新陈代谢可以通过多种方式影响我们的身体运作，而不仅仅是通过改变过度饮食卡路里转化为脂肪。一些代谢物充当信号或可用于改变基因的运作方式表达，它可以将饮食与我们的细胞功能及其应对压力的能力联系起来。我们提议研究一种代谢物 s-腺苷甲硫氨酸 (SAM) 如何同时激活免疫并限制细胞如何改变基因表达模式以应对病原体或其他压力。这些看似矛盾的功能的出现是因为 SAM 可用于不同的细胞需要。 SAM 可用于制造磷脂磷脂酰胆碱 (PC)，当 PC 有限时通过饮食或额外膜生产所需，大部分 SAM 用于这种生物合成过程。然而，组蛋白的修饰也需要 SAM。使用秀丽隐杆线虫，我们发现低 SAM 通过低 PC 激活标准实验室的先天免疫标志物饮食。然而，这些相同的动物无法在细菌挑战中生存，因为它们无法甲基化组蛋白启动基因激活并将病原体反应基因调至足够的水平水平。因此，不同的环境可以改变低 SAM 的表型，因为细胞需要优先考虑该代谢物的利用。我们的提案解决了几个关键问题。首先，不知道SAM和PC信号低是怎么回事免疫系统的激活。其次，尚不清楚全局染色质修饰是如何进行的第三，我们还不了解生理学上的变化低 SAM 的调节因子可能会影响这些表型中的任何一种。我们的线虫系统非常出色剖析这些机制的模型。我们将结合遗传和分子技术（包括染色质修饰的全基因组测定）和饮食调整以确定 SAM 如何与这些表型相关联。我们使用了 SAM 和 PC 相关的屏幕免疫调节剂以确定额外的监管成分并建议确定如何这些候选者可能与免疫激活有关。此外，我们还确定多种类型的应激诱导基因表达依赖于 SAM，并将使用该系统来询问如何 SAM 和利用它的组蛋白甲基转移酶在应激期间控制转录。虽然低 SAM 可以导致具有非常独特的分子机制的表型，例如脂质依赖性免疫反应中 MAP 激酶的激活和转录中组蛋白的修饰监管，一起研究这些过程很重要。饮食导致的 SAM 消耗可能会影响这些机制中的一种或两种，改变了我们的细胞对压力的反应方式。