Development and Applications of 'Designer Chromatin'

描述（由申请人提供）：将进行一项研究计划，以加深我们对染色质结构和功能调节的分子机制的理解。染色质是基因组DNA与组蛋白和非组蛋白的复合物，是所有真核生物基因组的生理相关形式。染色质曾经被认为只是DNA的包装溶液，现在被认为是调节DNA访问的动态信号平台。事实上，这项研究提案植根于这样一种想法，即存在染色质的可遗传功能“状态”，代表了在DNA本身之外运作的基本调控机制，有助于设定DNA的转录潜力。 基因座在建立和维持这些染色质状态时所犯的错误，由染色质重塑活动控制，导致基因的错误调节，对人类生物学和人类疾病具有深远的影响。在我们称之为“设计者染色质”的合成和应用方面的一些最新突破的基础上，我们将整合化学，生物化学，生物物理和遗传工具，以更深入地了解染色质功能调节的物理化学原理。当前的重点将是组蛋白泛素化在染色质生物学中的作用（目标1和2），然而，新的工具也将被开发，将这项工作的范围大大扩展到染色质调控的其他方面，重要的是，通过极大地加速机械生物化学（目标2和3）。在短期内，这项研究旨在揭示组蛋白泛素化协调染色质下游生物化学的分子机制，这一理解可能有助于合理设计针对抑制酶（如甲基转移酶hDot1L）治疗白血病的疗法。从长远来看，作为这项工作的一部分而开发的技术将在以下方面具有广泛的用途： 染色质区域。.

DESCRIPTION (provided by applicant): A research program will be undertaken to deepen our understanding of the molecular mechanisms underlying the regulation of chromatin structure and function. Chromatin, the complex of genomic DNA with histone and non-histone proteins, is the physiologically relevant form of all eukaryotic genomes. Once thought of as merely a packaging solution for the DNA, it is now accepted that chromatin serves as a dynamic signaling platform to regulate DNA access. Indeed, this research proposal is rooted in the idea that there exist heritable functional "states" of chromatin, representing a fundamental regulatory mechanism that operates outside of the DNA itself, that help set the transcriptional potential of a gene locus. Mistakes made in establishing and maintaining these chromatin states, governed by chromatin remodeling activities, lead to the misregulation of genes with far-reaching implications for human biology and human disease. Building on some recent breakthroughs on the synthesis and application of what we call 'designer chromatin', we will integrate chemical, biochemical, biophysical and genetic tools for the purpose of obtaining a deeper understanding of the physicochemical principles underlying the regulation of chromatin function. The immediate focus will be on the role of histone ubiquitylation in chromatin biology (aims 1 and 2), however, new tools will also be developed that broaden the scope of this work significantly into other aspects of chromatin regulation and, importantly, that do so by greatly accelerating mechanistic biochemistry (aims 2 and 3). In the short term, this research is designed to reveal the molecular mechanism(s) by which histone ubiquitylation orchestrates downstream biochemistry on chromatin, an understanding that may aid the rational design of therapeutics directed at inhibiting enzymes such as the methyltransferase, hDot1L, for the treatment of leukemias. In the long term, the technologies that will be developed as part of this work, will have broad utility in the chromatin area. .