NETWORKS, PATHWAYS AND DYNAMICS OF LYSINE MODIFICATION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 描述（由申请人提供）：组蛋白赖氨酸上的蛋白质修饰对于控制基因表达至关重要，基因表达本身控制蛋白质组在不同细胞类型中的可变和等离子表达。赖氨酸的修饰在化学上是多样的，包括乙酰化、甲基化、泛素化和类小泛素化。我们和其他人已经在许多其他蛋白质中发现了乙酰赖氨酸和甲基赖氨酸，只有一些直接控制基因表达;许多是关键的调节代谢酶。泛素化控制大多数蛋白质的生命和死亡，以及其他蛋白质功能。调节赖氨酸上不同修饰的途径非常复杂，还有很多东西有待了解。这些修饰途径之间的网络和动态相互作用更加复杂;许多赖氨酸修饰蛋白由多基因家族编码，具有冗余活性和多种底物，其中只有一些是已知的。修改之间的交互提供了额外的监管层。我们已经开发了基因，蛋白质芯片，化学，微流控和计算方法来解密和抽象这些信号通路定义的复杂网络，并监测它们如何随时间变化。该提案扩展了上一个预算期间开发的许多独特技术，特别侧重于使这些技术适用于监测一系列生物系统引起的动态蛋白质组变化。这些新的方法在网络和途径技术中心得到了补充，创新的质谱技术的应用，包括用于量化细胞中赖氨酸修饰动态的敏感和多样化的技术。酵母的代谢循环，结合细胞周期和DNA完整性是一个迷人的动态循环，将详细研究与几个技术。多样化的驱动生物项目集中在赖氨酸乙酰化，甲基化，泛素化和SUMOylafion，以及先进的培训工作。包括在波多黎各实习的学生，与技术开发方面的建议。技术和资源通过多种途径有效传播;静态和动态蛋白质组学数据集将集中存储/传播。相关性（参见说明）：组蛋白（及其他）上的赖氨酸修饰会影响基因表达的基本模式，并且在疾病状态下通常会发生紊乱;开发技术来监测它们如何变化是必不可少的。由于赖氨酸修饰与人类健康、衰老和疾病密切相关，网络和途径技术中心可能会产生深远的临床前和临床影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): Protein modification on histone lysines is critical for controlling gene expression, which itself controls the variable and plasfic expression ofthe proteome in diverse cell types. Modifications on lysine are chemically diverse and include acetylation, methylation, ubiquitylafion and sumoylation. We and others have discovered acetyl- and methyl-lysines in many other proteins, and only some directly control gene expression; many are critical regulatory metabolic enzymes. Ubiquitylation controls the life and death of most proteins, and other protein funcfions. The pathways regulating diverse modificafions on lysines are remarkably complex; much remains to be learned. The network of and dynamic interacfions among these modificafion pathways is even more complex; many lysine-modifying proteins are encoded by multi-gene families, have redundant activifies, and multiple substrates, only some of which are known. Cross-talk between modificafions provides an extra layer of regulation. We have developed genefic, protein chip, chemical, microfiuidic and computafional approaches to decrypt and abstract the complex networks defined by these signaling pathways and monitor how they change over time. This proposal extends many unique technologies developed in the last budget period, with a special focus on adapfing these technologies to monitoring dynamic proteomic changes occurring in response to a range of biological sfimuli. These newer approaches are complemented in this Technology Center for Networks and Pathways by applicafion of innovative mass spectrometry technologies, including sensitive and diverse technologies for quantifying dynamics of lysine modification in cells. The yeast metabolic cycle, integrated with cell cycling and DNA integrity is a fascinafing dynamic cycle that will be studied in detail with several ofthe technologies. Diverse Driving Biological Projects centered on lysine acetylation, methylation, ubiquitylafion and SUMOylafion, as well as advanced Training efforts. Including an internship for students in Puerto Rico, are integrated with the Technology Development aspects ofthe proposal. Technologies and resources are acfively disseminated via mulfiple routes; both static and dynamic proteomics datasets will be centrally warehoused/disseminated. RELEVANCE (See instructions): Lysine modification on histones (and beyond) affects fundamental patterns of gene expression and is often deranged in disease states; developing technologies to monitor how they change is essenfial. Because lysine modificafion is so extensively intertwined with human health, aging and disease, the Technology Center for Networks and Pathways could have far-reaching pre-clinical and clinical impact.