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影响我们的身体如何在许多方面的工作，而不仅仅是把多余的 卡路里转化为脂肪。一些代谢物作为信号，或可用于修改基因是如何表达的。 这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 我建议研究一种代谢物S-腺苷甲硫氨酸（SAM）如何既能激活 免疫力和限制细胞如何改变基因表达模式以响应病原体或其他 应力这些看似矛盾的功能发生，因为SAM可以用于不同的细胞 需求SAM可用于制备磷脂酰胆碱（PC），当PC有限时， 由饮食或需要额外的膜生产，大部分SAM用于这种生物合成 过程然而，SAM也需要用于组蛋白的修饰。利用C.我们发现， 在标准实验室中，低SAM通过低PC激活先天免疫标志物 饮食.然而，这些动物无法在细菌挑战中存活，因为它们不能 甲基化组蛋白引发基因激活，并使病原体应答基因对足够的 程度.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 利用这种代谢产物。 我们的建议涉及几个关键问题。首先，目前尚不清楚低SAM和PC信号 激活免疫系统。第二，不了解全局染色质修饰如何 第三，我们还不知道在低SAM下， 低SAM的调节子可能会影响这些表型中的任何一种。我们的线人elegans系统是一个优秀的 剖析这些机制的模型。我们将联合收割机结合基因和分子技术 （包括染色质修饰的全基因组测定）， SAM是如何与这些表型联系在一起的我们已经使用屏幕为SAM和PC依赖 免疫调节剂，以确定额外的调节成分，并提出如何确定 这些候选者可能与免疫激活有关。此外，我们已经确定， 多种类型的胁迫诱导的基因表达依赖于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胁迫期间控制转录。虽然低 SAM可以引起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，重要的是一起研究这些过程。由于饮食导致的SAM消耗可能会影响 这两种机制中的一种或两种，改变了我们的细胞对压力的反应。