Modeling Chromatin Organization and Function

描述（由申请人提供）：了解染色体组织及其对基因表达的控制代表了最基本和最重要的开放生物学挑战之一。在不同的空间和时间尺度上模拟染色质的折叠状态是解开最基本的细胞功能的关键，包括转录激活，基因沉默和表观遗传控制。在这项提案中，我们继续我们的创新建模项目染色质建模始于2000年，提供了关于染色质组织和动力学的新颖和高影响力的出版物，以纳入新的因素，扩大模型范围和影响重大的生物学问题。我们还增加了一位实验合作者，Sergei Grigoryev博士，我们已经成功地与他合作，[以及斯坦福大学Simbios国家生物医学计算中心的一个团队，以帮助传播我们的软件工具并增强我们项目的影响力。 我们的长期目标是整合染色质组织的结构和动力学方面，以描绘通过蛋白质因子，表观遗传标记和环境条件介导的转录调控的热力学机制。为了推进这一目标，我们将研究：（目的1）染色质结构和折叠与多价离子和动态离子分布;（目的2）染色质二级结构折叠在不同的内部和外部因素;（目的3）三级染色质组织与二价离子，染色质纤维浓度，和建筑蛋白。在目标1中，我们将开发一个严格的模型，染色质折叠与多价离子的组合使用泊松-玻尔兹曼理论，一个改进的表示筛选潜力的功能，和方法计算筛选潜力的染色质构象的变化。在目标2中，我们将探索DNA接头长度变异性、组蛋白变体、表观遗传修饰和外力对30 nm染色质纤维结构的影响[使用中尺度、多分辨率和全原子模型的创新组合]。在目标3中，我们将模拟由多价离子，集中的纤维环境和结合蛋白诱导的三级染色质结构，以解开纤维-纤维相互作用和纤维环形成的结构机制，并通过染色质折叠的大规模改变来促进我们对转录控制的理解。 这些具有挑战性的研究描绘染色质组织，充满活力，并与创新的建模和实验技术检查动态，将有助于阐明从根本上调节基因组组织和表达的关键结构/功能连接。与格里戈里耶夫博士的实验合作将有助于整合实验和理论;斯坦福大学Simbios的Altman将帮助传播我们开发的工具并增强项目影响力。所开发的模型和方法也适用于其他复杂大分子系统。最终，这项工作的结果通过影响控制核小体组成和染色质折叠的试剂的设计而具有实际应用。

DESCRIPTION (provided by applicant): Understanding chromosome organization and its control of gene expression represents one of the most fundamental and significant open biological challenges. Modeling the folding states of chromatin on various spatial and temporal scales is key for unraveling the most basic cellular functions, including transcription activation, gene silencing, and epigenetic control. In this proposal, we continue our innovative modeling project on chromatin modeling started in 2000 that has provided novel and high-impact publications concerning chromatin organization and dynamics to incorporate new factors that expand the model scope and impact significant biological problems. We also add an experimental collaborator, Dr. Sergei Grigoryev, with whom we have already worked successfully, [and a team at Stanford's Simbios National Center for Biomedical Computation, to help disseminate our software tools and enhance our project's impact.] Our long term goal is to integrate structural and dynamical aspects of chromatin organization to delineate the thermodynamic mechanisms of transcriptional regulation mediated through protein factors, epigenetic marks, and environmental conditions. To advance in this goal, we will study: (Aim 1) chromatin structure and folding with multivalent ions and dynamic ionic distribution; (Aim 2) chromatin secondary structure folding under different internal and external factors; (Aim 3) tertiary chromatin organization with divalent ions, chromatin fiber concentration, and architectural proteins. In Aim 1, we will develop a rigorous model of chromatin folding with multivalent ions by using a combination of Poisson-Boltzmann theory, an improved representation of screening potential functions, and a method for computing screening potentials as the chromatin conformation changes. In Aim 2, we will explore the effects in the structure of the 30-nm chromatin fiber of DNA linker length variability, histone variants, epigenetic modifications and external forces [using an innovative combination of mesoscale, multiresolution and all-atom models.] In Aim 3, we will model tertiary chromatin structures induced by multivalent ions, concentrated fiber environments, and bound proteins to unravel the structural mechanisms for fiber-fiber interactions and fiber-loop formation and advance our understanding of transcriptional control via large-scale alterations of chromatin folds. These challenging studies in delineating chromatin organization, energetic, and dynamics examined with innovative modeling and experimental techniques, will help elucidate key structure/function connections that fundamentally regulate genomic organization and expression. The experimental collaboration with Dr. Grigoryev will help integrate experiment and theory; [the collaboration with Dr. R. Altman at Stanford's Simbios will help disseminate our developed tools and enhance project impact.] The developed models and methods are applicable to other complex macromolecules systems. Ultimately, this work's results have practical applications by impacting design of agents that control nucleosome composition and chromatin folds.