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

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 因子和转录机制与动态访问，否则紧密包装的基因组。 许多染色质修饰酶需要代谢物作为辅因子;因此，细胞代谢状态 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，以允许细胞和生物体响应环境 条件我们正在利用拟南芥研究乙烯的代谢状态和染色质调控 发信号。我们的小组开创了乙烯信号传导中组蛋白调节的研究。乙烯信号是 在内质网（ER）膜上被感知，以及EIN 2的切割和核转位 介导从内质网膜到细胞核的信号。EIN 2 C-末端（EIN 2-C）被切割， 转移到细胞核引发乙烯反应。在上一个融资周期，我们 发现EIN 2是一种重要的信号传导因子，也是组蛋白的关键成分。 直接调节H3 K14 Ac和H3 K23 Ac以介导转录反应的修饰 乙烯。因此，EIN 2是乙烯信号传导和染色质调节之间的直接联系。我们 还鉴定了一种非经典的含组蛋白乙酰转移酶（HAT）结构域的蛋白EHAT， 直接与细胞核中的EIN 2-C相互作用。我们的初步数据强烈表明，EHAT链接 EIN 2介导的乙烯信号传导与EIN 2介导的组蛋白乙酰化调节。引人注目的是，我们的新 数据提供了确凿的证据，即转化丙酮酸的丙酮酸脱氢酶复合物 乙酰辅酶A，组蛋白乙酰化的乙酰供体，与EIN 2-C相互作用， 复合物的一部分可以从线粒体转移到细胞核中以响应乙烯。这 一项新的发现为乙酰辅酶A生物合成参与细胞凋亡的假说提供了强有力的理论依据。 EIN 2介导的染色质调节和乙烯信号传导之间的相互作用。在本提案中，我们将 研究代谢状态和染色质调节乙烯信号通过关注以下具体 目的：（1）阐明EIN 2依赖性组蛋白修饰的详细机制， 研究EIN 2 - 1中代谢酶丙酮酸脱氢酶（pyruvate dehydrogenase，PKD）的功能。 介导的染色质和转录调节响应乙烯，和（3）阐明分子 EIN 2-C在乙烯作用下转移到细胞核的机制。我们的工作将 具有广泛的影响，因为核过程的功能障碍直接导致癌症进展， 遗传疾病和代谢与染色质活性之间的失衡可引发严重的代谢紊乱， 疾病

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.