Regulation of Chromatin by Histone Phosphorylation

 描述(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性质和效应蛋白的结合，从而调节生物过程，包括转录、有丝分裂染色体紧凑和分离，以及DNA损伤的修复。染色质研究中的一个基本挑战是了解PTM组合调控染色质过程的机制。组蛋白磷酸化的研究是本研究的重点，组蛋白磷酸化是一种高度带电的PTM，具有很大的调节组蛋白调节过程的潜力。拟议的研究计划的总体目标是应用最先进的和新颖的实验方法来了解组蛋白磷酸化在细胞周期进程和转录调控中染色质过程调节中的作用。在培训期间，我将表征组蛋白PTM的组合，将组蛋白磷酸化作为一种预测的调节开关，通过培训期间和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“即刻-早期基因”激活相关，但对磷酸化在快速转录反应中所起作用的机制缺乏了解。随着新工具的开发，以及重要的是，通过我在指导期间所描述的培训，我提出的研究承诺应用不同的方法来揭示新的磷酸化组蛋白修饰的基因的转录机制的快速招募和活动的新见解。最后，通过结合计算和比较基因组学技术以及我将在培训期间掌握的生化方法，我建议在我职业生涯的独立阶段研究快速转录反应的更广泛的机制和进化，以与刺激时组蛋白磷酸化相关的调控DNA元件为指导。组蛋白磷酸化是环境信号转导到染色质的主要机制，具有独特的生物物理性质和显著改变组蛋白-“阅读器”分子相互作用的潜力，在不同的生物过程中产生影响。

 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.