Regulation of Chromatin by Histone Phosphorylation

 描述（由申请人提供）：组蛋白翻译后修饰（PTM）可以改变染色质的生物物理特性和效应蛋白的结合，从而调节生物学过程，包括转录、有丝分裂染色体压实和分离以及DNA损伤的修复。染色质研究中的一个根本挑战是了解PTM组合调节染色质过程的机制。组蛋白磷酸化是一种高度带电的PTM，具有调节组蛋白调节过程的巨大潜力，是本研究的重点。拟议的研究计划的总体目标是应用最先进的和新的实验方法，以了解组蛋白磷酸化在细胞周期进程和转录调控中的染色质过程的调节作用。在培训期间，我将描述组蛋白PTM的组合，组蛋白磷酸化作为预测的调节开关，并通过培训期间，进入我职业生涯的独立阶段，我将研究它们在不同生物过程中的作用。虽然组蛋白磷酸化长期以来一直与“立即早期基因”激活相关，但缺乏对磷酸化在快速转录反应中作用的机制理解。随着新工具的发展，重要的是，我在指导期间描述的培训，我提出的研究有望应用不同的方法来揭示新的见解，快速招聘和转录机制在新磷酸化组蛋白修饰的基因的活动。最后，通过结合计算和比较基因组学技术和生化方法，我将在培训期间掌握，我建议研究，到我的职业生涯的独立阶段，更广泛的机制和快速转录反应的演变，作为指导的调控DNA元件，与组蛋白磷酸化刺激。组蛋白磷酸化，其独特的生物物理特性和潜在的显着改变组蛋白-“读者”分子的相互作用，是一个主要的机制，环境信号转导到染色质的后果，在不同的生物过程。

 DESCRIPTION (provided by applicant): Histone post-translational modifications (PTMs) can alter the biophysical properties of chromatin and the binding of effector proteins, thereby regulating biological processes including transcription, mitotic chromosome compaction and segregation, and repair of DNA damage. A fundamental challenge in chromatin research is to understand the mechanisms by which combinations of PTMs regulate chromatin processes. The study of histone phosphorylation, a highly charged PTM with great potential to modulate histone-regulated processes, is the focus of this research. The overall goal of the proposed research plan is to apply state of the art and novel experimental approaches to understand the role of histone phosphorylation in the regulation of chromatin processes in cell cycle progression and transcriptional regulation. During the training period I will characterize combinations of histone PTMs, with histone phosphorylation as a predicted regulatory switch, and through the training period and into the independent phase of my career, I will study their role in diverse biological processes. While histone phosphorylation has long been correlated with "immediate-early gene" activation, mechanistic understanding of the role of phosphorylation in the rapid transcription response is lacking. With the development of new tools, and importantly, with the training that I describe during the mentored period, my proposed research promises to apply diverse approaches to reveal new insights into the rapid recruitment and activity of transcription machinery at genes decorated by newly phosphorylated histones. Finally, through the combination of computational and comparative genomics techniques and biochemical approaches that I will master during the training period, I propose to study, into the independent phase of my career, the broader mechanisms and evolution of the rapid transcription response, using as a guide the regulatory DNA elements that are associated with histone phosphorylation upon stimulation. Histone phosphorylation, with its distinct biophysical properties and potential to dramatically alter histone-"reader" molecular interactions, is a principal mechanism for the transduction of environmental signals to chromatin with consequences in diverse biological processes.