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: 8716548
• 负责人: Stacey Borrego
• 金额: $ 3.68万
• 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/8716548
• 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-腺苷蛋氨酸(SAM)是由蛋氨酸和三磷酸腺苷合成的，参与的细胞反应比除三磷酸腺苷以外的任何其他分子都多。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。预测一个细胞系统来监测细胞内SAM浓度并防止启动 当SAM水平太低时细胞分裂，以确保S期染色质甲基化的忠实复制。这个概念让人联想到细胞周期检查点的概念，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浓度以及这些信息如何被传递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水平降至临界阈值浓度以下时，DNA复制是如何被阻止的。我的假设是，SAM感知与少数“感觉”蛋白质的翻译控制有关。我认为这些感觉蛋白的特定mRNAs是在mRNA帽甲基化水平上进行调节的。这种调节的机制将通过从经历SAM限制的细胞中纯化N7甲基帽的mRNAs来解决。此外，已经开发了模型，使我能够解决关于表观遗传稳定性和饮食限制对表观遗传学的影响的基本问题。为了评估表观遗传稳定性，我将使用经过修改以避开SAM检查点的酵母报告菌株，并在SAM限制条件下监测酵母细胞的组蛋白甲基化。使用可诱导的击倒蛋氨酸腺苷转移酶的类似实验将解决哺乳动物系统中的相关问题。蛋氨酸腺苷转移酶是负责SAM合成的酶。在我的论文工作中，我建议对细胞如何监测细胞内SAM浓度以及这些信息如何被传递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的细胞周期检查点的范例，并将探讨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是如何与细胞功能相联系的 分子水平。我的建议特别涉及代谢途径的相互作用和表观遗传信息的稳定性。结果可能会对我们理解饮食因素和补充剂，如相同的，叶酸，或维生素B12有重要的影响。我的论文提案将只开始将营养失衡作为表观遗传变化的一个因素来解决。然而，我将开发工具，允许其他人扩大对营养素和表观遗传学之间相互作用的研究。