Investigate the molecular mechanisms of the interplay between cell metabolism and histone modification in ethylene signaling in Arabadopsis

研究拟南芥乙烯信号传导中细胞代谢与组蛋白修饰相互作用的分子机制

• 批准号: 10117420
• 负责人: Hong Qiao
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117420
• 关键词: Acetyl Coenzyme A; Anabolism; Arabidopsis; Binding; Biochemical; Cell Nucleus; Cells; Cellular Metabolic Process; Chromatin; Chromatin Structure; Cleaved cell; Complex; Cues; DNA Sequence; Data; Disease; Endoplasmic Reticulum; Environment; Enzymes; Epigenetic Process; Ethylenes; Eukaryota; Fruit; Functional disorder; Funding; Gene Expression; Gene Expression Regulation; Genetic; Genetic Diseases; Genetic Transcription; Genome; Genomic approach; Germination; Goals; Histone Acetylation; Histones; Hormones; Life Cycle Stages; Link; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Modification; Molecular; Nuclear; Nuclear Translocation; Organism; Phenotype; Plant Leaves; Plants; Play; Process; Protein Dephosphorylation; Proteins; Pyruvate; Pyruvate Dehydrogenase Complex; Regulation; Role; Seedling; Seeds; Signal Transduction; Solid; Transcriptional Regulation; Work; cancer genetics; chromatin remodeling; cofactor; functional genomics; histone acetyltransferase; histone modification; histone-binding proteins; hormonal signals; metabolic abnormality assessment; pyruvate dehydrogenase; recruit; response; senescence; transcription factor; tumor progression

Project Summary Nuclear enzymes, chromatin and its modifications mediate the responses of cells and organisms to dynamic environments. Chromatin remodeling influences gene expression by providing transcription factors and the transcription machinery with dynamic access to an otherwise tightly packaged genome. Many chromatin-modifying enzymes require metabolites as cofactors; therefore, the cell metabolic state can influence chromatin structure and epigenetic processes. However, little is known about how metabolic states and chromatin regulation are coordinated to allow cells and organisms to respond to environmental conditions. We are using Arabidopsis to study the metabolic states and chromatin regulation in ethylene signaling. Our group pioneered the study of histone regulation in ethylene signaling. The ethylene signal is perceived on the endoplasmic reticulum (ER) membrane, and the cleavage and nuclear translocation of EIN2 mediates the signal from the ER membrane to the nucleus. The EIN2 C-terminus (EIN2-C) is cleaved and translocated to the nucleus to initiate the ethylene response. During the last funding period, we discovered that EIN2, an essential signaling factor, is also a key component of the histone modification that directly regulates H3K14Ac and H3K23Ac to mediate the transcriptional response to ethylene. EIN2 is thus the direct link between ethylene signaling and chromatin regulation. We also identified a noncanonical histone acetyltransferase (HAT) domain-containing protein EHAT that directly interacts with the EIN2-C in the nucleus. Our preliminary data strongly suggest that EHAT links EIN2-mediated ethylene signaling with EIN2-meidated regulation of histone acetylation. Strikingly, our new data provide solid evidence that the pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA, the acetyl-donor of histone acetylation, interacts with EIN2-C and that the subunits of the complex can translocate from the mitochondria to the nucleus in response to ethylene. This new discovery provides a strong rational for the hypothesis that acetyl-CoA biosynthesis is involved in the EIN2-mediated interplay between chromatin regulation and ethylene signaling. In this proposal, we will study metabolic states and chromatin regulation in ethylene signaling by focusing on the following specific aims: (1) elucidate the detailed mechanisms governing EIN2-dependent histone modification in response to ethylene; (2) investigate the function of the metabolic enzyme pyruvate dehydrogenase in EIN2- mediated chromatin and transcriptional regulation in response to ethylene, and (3) elucidate the molecular mechanisms by which the EIN2-C is translocated to the nucleus in response to ethylene. Our work will have broad implications as dysfunctions of nuclear processes contribute directly to cancer progression and genetic disorders and imbalances between metabolism and chromatin activities can trigger severe metabolic disease.

项目摘要 核酶、染色质及其修饰介导细胞和生物体对 动态环境。染色质重塑通过提供转录影响基因表达 因子和转录机制，能够动态访问原本紧密包装的基因组。 许多染色质修饰酶需要代谢物作为辅助因子；因此，细胞的代谢状态 可以影响染色质结构和表观遗传过程。然而，人们对新陈代谢是如何进行的知之甚少。 状态和染色质调节是协调的，以允许细胞和有机体对环境做出反应 条件。我们正在利用拟南芥来研究乙烯的代谢状态和染色质调节 发信号。我们小组率先研究了组蛋白在乙烯信号中的调节。乙烯信号是 在内质网(ER)膜上观察到，以及EIN2的切割和核转位 将信号从内质网膜传递到细胞核。EIN2-C末端(EIN2-C)被切割并 转移到细胞核以启动乙烯反应。在上一个资助期内，我们 发现EIN2，一个重要的信号因子，也是组蛋白的一个关键成分 直接调节H3K14Ac和H3K23Ac以介导转录反应的修饰 到乙烯。因此，EIN2是乙烯信号和染色质调节之间的直接联系。我们 还鉴定了一种含有组蛋白乙酰转移酶(HAT)结构域的非规范性蛋白EHAT 直接与胞核中的EIN2-C相互作用。我们的初步数据有力地表明， EIN2介导的乙烯信号转导与EIN2调控组蛋白乙酰化。引人注目的是，我们的新产品 数据提供了确凿的证据，丙酮酸脱氢酶复合体转化为丙酮酸 组蛋白乙酰化的乙酰化供体乙酰辅酶A与EIN2-C相互作用，其亚基 该复合体的一部分可以对乙烯作出反应，从线粒体移位到细胞核。这 新的发现为乙酰辅酶A的生物合成参与植物生长的假说提供了强有力的依据。 EIN2介导的染色质调节和乙烯信号之间的相互作用。在这项提案中，我们将 研究乙烯信号转导中的代谢状态和染色质调节 目的：(1)阐明EIN2依赖的组蛋白修饰反应的详细机制 (2)研究EIN2-代谢酶丙酮酸脱氢酶的功能。 介导染色质和转录调控对乙烯的响应，以及(3)阐明分子 EIN2-C对乙烯的反应被转移到核的机制。我们的工作将 有广泛的影响，因为核过程的功能障碍直接导致癌症的进展和 遗传性疾病以及新陈代谢和染色质活动之间的不平衡会引发严重的代谢。 疾病。