Integration of S-adenosylmethionine Metabolism with Epigenetics and Cell Cycle

S-腺苷甲硫氨酸代谢与表观遗传学和细胞周期的整合

• 批准号: 8459897
• 负责人: Stacey Borrego
• 金额: $ 3.64万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459897
• 关键词: Address; Apoptosis; Biochemical; Biochemical Pathway; Biochemical Reaction; Biological Preservation; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell division; Cell physiology; Cells; Chromatin; Communication; Culture Media; DNA biosynthesis; DNA damage checkpoint; Dependency; Diet; Dietary Factors; Drug Targeting; Ensure; Enzymes; Epigenetic Process; Event; Folate; Future; Gene Expression; Genetic; Genetic Transcription; Growth; Histones; Homocysteine; Homocystine; Hypersensitivity; Laboratories; Lead; Life; Link; Maintenance; Malignant Neoplasms; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methylation; Modeling; Molecular; Molecular Biology; Monitor; Normal Cell; Nutrient; Organism; Pathway interactions; Pre-Replication Complex; Proliferating; Proteins; RNA; Reaction; Regulation; Reporter; Research; S Phase; S-Adenosylmethionine; Sensory; Signaling Molecule; System; Therapeutic; Translations; Vitamin B 12; Work; Yeasts; cancer cell; dietary supplements; experience; falls; innovation; insight; interest; killings; knock-down; mRNA capping; methionine adenosyltransferase; novel; novel strategies; novel therapeutics; prevent; public health relevance; research study; tool; transmission process

DESCRIPTION (provided by applicant): The principal methyl-donor S-adenosylmethionine (SAM) is synthesized from methionine and ATP, and participates in more cellular reactions than any other molecule except for ATP. As the co-factor for all chromatin methylation events, SAM is critical for the maintenance and transmission of epigenetic information. It is reasonable to predict a cellular system that monitors intracellular SAM concentrations and prevents initiation of cell division when SAM levels are too low to ensure faithful duplication of chromatin methylation during S-phase. This concept is reminiscent of the cell cycle checkpoint idea and we thus refer to it as the SAM-checkpoint. For my thesis work I propose to generate a molecular understanding for how cells monitor intracellular SAM concentrations and how this information is transmitted to the cell cycle machinery to induce the SAM-checkpoint. I will examine how cells monitor intracellular SAM levels and how DNA replication is blocked when SAM levels fall below a critical threshold concentration. My hypothesis is that SAM sensing is linked to translational control of a small number of "sensory" proteins. I suggest that select mRNAs of these sensory proteins are regulated at the level of mRNA cap methylation. The mechanism of this regulation will be addressed via purification of N7 methyl-capped mRNAs from cells experiencing SAM limitation. Furthermore, models have been developed that will allow me to address fundamental questions about epigenetic stability and the effect of dietary limitations on epigenetics. To assess epigenetic stability I will use yeast reporter strains modified to evade the SAM-checkpoint and monitor histone methylation of yeast cells in SAM limiting conditions. Similar experiments using inducible knock-down of methionine adenosyltransferase, the enzyme responsible for SAM synthesis, will address related questions in the mammalian system. For my thesis work I propose to generate a molecular understanding for how cells monitor intracellular SAM concentrations and how this information is transmitted to the cell cycle machinery to induce the SAM-checkpoint. This research may generate a paradigm for metabolite-regulated cell cycle checkpoints and will approach fundamental questions about epigenetics. My proposed studies will generate a first insight into how metabolic pathways are connected to cell function at the molecular level. My proposal specifically addresses the interaction of metabolic pathways and stability of epigenetic information. Results may have important consequences for our understanding of dietary factors and supplements such as SAMe, folates, or vitamin B12. My thesis proposal will only begin to address nutrient imbalance as a factor of epigenetic changes. However, I will develop tools to allow others to expand research on the interaction between nutrients and epigenetics.

描述（申请人提供）：主要的甲基供体S-腺苷甲硫氨酸（SAM）是由甲硫氨酸和ATP合成的，并且比除ATP之外的任何其他分子参与更多的细胞反应。作为所有染色质甲基化事件的辅助因子，SAM 对于表观遗传信息的维持和传递至关重要。可以合理地预测一个细胞系统可以监测细胞内 SAM 浓度并防止启动 当 SAM 水平太低而无法确保 S 期染色质甲基化的忠实复制时，细胞分裂。这个概念让人想起细胞周期检查点的想法，因此我们将其称为 SAM 检查点。在我的论文工作中，我建议对细胞如何监测细胞内 SAM 浓度以及如何将这些信息传输到细胞周期机制以诱导 SAM 检查点产生分子理解。我将研究细胞如何监测细胞内 SAM 水平，以及当 SAM 水平低于临界阈值浓度时 DNA 复制如何被阻断。我的假设是 SAM 传感与少量“感觉”蛋白质的翻译控制有关。我建议这些感觉蛋白的选择性 mRNA 在 mRNA 帽甲基化水平上受到调节。这种调节的机制将通过从经历 SAM 限制的细胞中纯化 N7 甲基加帽的 mRNA 来解决。此外，已经开发出的模型将使我能够解决有关表观遗传稳定性和饮食限制对表观遗传学影响的基本问题。为了评估表观遗传稳定性，我将使用经过修饰的酵母报告菌株来逃避 SAM 检查点并在 SAM 限制条件下监测酵母细胞的组蛋白甲基化。使用蛋氨酸腺苷转移酶（负责 SAM 合成的酶）诱导敲低的类似实验将解决哺乳动物系统中的相关问题。在我的论文工作中，我建议对细胞如何监测细胞内 SAM 浓度以及如何将这些信息传输到细胞周期机制以诱导 SAM 检查点产生分子理解。这项研究可能会产生代谢物调节细胞周期检查点的范例，并将解决有关表观遗传学的基本问题。我提出的研究将首次深入了解代谢途径与细胞功能的关系 分子水平。我的建议特别涉及代谢途径和表观遗传信息稳定性的相互作用。结果可能对我们了解饮食因素和补充剂（例如 SAMe、叶酸或维生素 B12）产生重要影响。我的论文提案只会开始解决营养失衡作为表观遗传变化的一个因素。然而，我将开发工具，让其他人能够扩大对营养素和表观遗传学之间相互作用的研究。