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: 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
• 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

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的身体工作方式，而不仅仅是使多余的 卡路里变成脂肪。一些代谢物作为信号，或可用于修改基因的方式 表达，可以将饮食与我们的细胞的功能和对压力的反应能力联系起来。我们 建议研究一种代谢物，S-腺苷甲硫代氨酸（SAM）如何激活标记 免疫力并限制细胞如何根据病原体或其他方式改变基因表达模式 压力。这些看似悖论的功能之所以发生，是因为SAM可用于不同的细胞 需要。 SAM可用于使磷脂磷脂酰胆碱（PC）和PC有限时 通过饮食或额外产生的额外产生，大部分SAM用于这种生物合成 过程。但是，还需要SAM来修饰组蛋白。使用秀丽隐杆线虫，我们发现 Low Sam通过低PC作用以激活标准实验室的先天免疫标记 饮食。但是，这些相同的动物无法在细菌挑战中幸存下来，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变为足够 水平。因此，不同的上下文可以改变低SAM的表型，因为细胞需要优先级 利用这种代谢物。 我们的建议解决了几个关键问题。首先，尚不知道低SAM和PC信号如何 免疫系统的激活。其次，尚不了解全局染色质的修饰 在压力下可能会在低山姆和第三个变化，我们还不了解生理 低SAM的调节剂可能会影响这两种表型。我们的秀丽隐杆线虫系统是一个极好的 解剖这些机制的模型。我们将结合遗传和分子技术 （包括整个基因组修饰的基因组测定）进行饮食修饰以确定 SAM如何与这些表型联系在一起。我们已经使用了SAM和PC依赖性的屏幕 免疫的修饰符，以识别其他调节组件，并提出确定如何确定 这些候选物可能与免疫激活有关。此外，我们已经确定 多种类型的压力引起的基因表达取决于SAM，并将使用该系统询问如何 SAM和组蛋白甲基转移酶在应力过程中利用IT控制转录。虽然很低 SAM可以引起具有非常不同分子机制的表型，例如脂质依赖性 在转录中的免疫反应和修饰中，MAP激酶的激活 调节，重要的是一起研究这些过程。由于饮食而导致的SAM耗尽可能会影响 这些机制中的任何一个或两个都改变了我们的细胞对压力的反应方式。