Discovery and functional characterization of the hypoxia-responsive methyllysine proteome

对于许多生物来说，生存取决于适应温度，氧气和水供应的环境变化。在这些压力中，大多数后生动物的生存本质上与氧气的可用性有关，因此已经进化出在环境中严重减少的情况下生存的机制。在人类中，氧限制最常在高海拔、发育期间以及在许多临床病症（诸如中风、高血压、缺血性心脏病和急性心肌梗死）中遇到。在细胞应激期间，蛋白质的可逆翻译后修饰（PTM）为细胞提供了快速改变其细胞环境并调节蛋白质功能以响应各种刺激的能力。最近探索翻译后赖氨酸（Lys）甲基化作用的研究表明，动态甲基化以与其他PTM类似的方式发挥作用，作为快速调节蛋白质功能和生物学过程的一种手段。参与低氧敏感和生物体存活的几种途径，包括HIF-1（低氧诱导因子-1），未折叠蛋白反应，以及NF-κ B和PI 3 K-Akt信号通路最近已被证明通过Lys甲基化进行可逆调节，然而，在低氧应激下这些途径的甲基化诱导的调节之间的联系尚未被探索。虽然最近的研究已经确定，赖氨酸甲基化是一种普遍的PTM与不同的功能作用，我们才刚刚开始描绘的范围内的甲基赖氨酸蛋白质组和全谱的细胞和发育过程，它可以调节。迄今为止，甲基化研究主要集中在发现赖氨酸甲基化蛋白和修饰位点，对其生物学后果知之甚少。我在低氧生物学方面的研究专长，加上我在功能蛋白质组学和赖氨酸甲基化发现方面的博士后研究，使我的研究工作处于前所未有的地位，以推进对蛋白质甲基化如何调节低氧环境中生存的基本理解。我的实验室将专注于汇集比较应激生物学，功能蛋白质组学和生物信息学，以发现和分配生物学意义的翻译后赖氨酸甲基化的基本调节途径和信号网络，使细胞在缺氧（1% O2）中生存。 我的研究贡献不仅将使我们对低氧应激反应，蛋白质甲基化和功能有基本的了解，而且还将发现赖氨酸甲基化蛋白质如何促进和协调对人类最基本和威胁生命的压力之一的反应-氧限制。

For many organisms, survival is dependent upon adapting to environmental variability in temperature, oxygen, and water supply. Among these stresses, survival of most metazoans is inherently tied to the availability of oxygen, such that mechanisms have evolved to survive severe reductions in the environment. In humans, oxygen restriction is most commonly encountered at high altitudes, during development, and in many clinical conditions such as stroke, hypertension, ischemic heart disease, and acute myocardial infarction. During periods of cell stress, the reversible post translational modification (PTM) of proteins provide cells with the ability to rapidly modify their cellular environment and regulate protein function in response to various stimuli. Recent research exploring the role of post translational lysine (Lys) methylation has shown that dynamic methylation functions in a similar manner to other PTMs, as a means to rapidly regulate protein function and biological processes. Several pathways involved in low oxygen sensing and organismal survival, including HIF-1 (hypoxia-inducible factor-1), the unfolded protein response, as well as NFkb and PI3K-Akt signaling pathways have been recently documented to undergo reversible regulation by Lys methylation, however the link between methylation-induced regulation of these pathways under low oxygen stress have not yet been explored. Although studies have recently established that Lys methylation is a prevalent PTM with diverse functional roles, we have only just begun to delineate the extent of the methyllysine proteome and the full spectrum of cellular and developmental processes that it can regulate. To date, methylation research has been primarily focused on the discovery of Lys methylated protein and modification sites, with little knowledge of its biological consequence. My research expertise in low oxygen biology, paired with my postdoctoral research in functional proteomics and Lys methylation discovery, place my research effort in an unprecedented position to advance the basic understanding of how protein methylation regulates survival in low oxygen environments. My lab will focus on bringing together comparative stress biology, functional proteomics, and bioinformatics to discover and assign biological significance to post translational Lys methylation in the fundamental regulation of pathways and signaling networks that enable cells to survive hypoxia (1% O2). My research contributions will not only empower our basic understanding of low oxygen stress response, protein methylation, and function, but will also discover how Lys methylated proteins contribute and coordinate the response to one of the most fundamental and life-threatening stresses to humans - oxygen limitation.