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

• 批准号: 9923536
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923536
• 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; histone methylation; histone methyltransferase; histone modification; immune activation; innate immune function; insight; p38 Mitogen Activated Protein Kinase; pathogen; response; transcriptome sequencing; whole genome

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在许多方面影响我们身体的工作方式，而不仅仅是通过过量 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是如何 它可以将饮食与我们的细胞如何运作以及它们应对压力的能力联系起来。我们 建议研究一种代谢物S-腺苷蛋氨酸如何同时激活两种标志物 免疫和限制细胞如何改变基因表达模式以响应病原体或其他 压力。这些看似矛盾的功能之所以会出现，是因为SAM可以用于不同的细胞 需要。SAM可用于制备磷脂磷脂酰胆碱(PC)，当PC受到限制时 通过饮食或额外的膜生产所需，SAM的大部分被用于这种生物合成 进程。然而，组蛋白的修饰也需要SAM。利用线虫，我们发现 低SAM通过低PC激活标准实验室的天然免疫标记物 节食。然而，这些动物无法在细菌挑战中幸存下来，因为它们不能 甲基化组蛋白启动基因激活并使病原菌反应基因充分 级别。因此，不同的上下文可以改变低SAM的表型，因为单元需要区分优先级 利用这种代谢物。 我们的建议解决了几个关键问题。首先，尚不清楚低SAM和PC如何发出信号 激活免疫系统。第二，目前还不清楚全球染色质修饰是如何 压力下的SAM可能会发生变化，第三，我们还不知道生理上的 低SAM的调节剂可能影响这两种表型中的任何一种。我们的线虫系统是一个极好的 剖析这些机制的模型。我们将把基因和分子技术结合起来 (包括染色质修饰的全基因组分析)和饮食修饰来确定 SAM是如何与这些表型相联系的。我们对SAM和PC依赖使用了屏幕 免疫力的修饰物，以确定额外的监管成分，并建议确定如何 这些候选基因可能与免疫激活有关。此外，我们已经确定， 多种类型的压力诱导的基因表达依赖于SAM，并将使用这个系统来询问如何 SAM和利用它的组蛋白甲基转移酶在应激状态下控制转录。虽然很低 SAM可以导致具有非常不同的分子机制的表型，例如脂质依赖 MAP激酶在免疫反应中的激活和转录中组蛋白的修饰 监管，重要的是把这些过程放在一起研究。饮食导致的SAM耗尽可能会影响 这两种机制中的一种或两种都会改变我们的细胞对压力的反应方式。