Mechanisms and functions of chromatin regulation for cell-cycle control

细胞周期控制染色质调控的机制和功能

• 批准号: 10015288
• 负责人: TOSHIO TSUKIYAMA
• 金额: $ 36.21万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015288
• 关键词: 3-Dimensional; Address; Affect; Binding; Biological; Cancer Biology; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Maintenance; Cell Nucleus; Cell Survival; Cell division; Cells; Chromatin; Chromatin Fiber; Chromatin Structure; DNA; DNA Repair; DNA biosynthesis; DNA damage checkpoint; Development; Eukaryotic Cell; Fiber; Fibroblasts; Funding; Genetic Recombination; Genetic Transcription; Genome Stability; Goals; Higher Order Chromatin Structure; Histone Deacetylase; Human; Kinetochores; Knowledge; Maintenance; Malignant Neoplasms; Messenger RNA; Methods; Mitotic Cell Cycle; Modeling; Molecular; Mutation; Nucleosomes; Organism; Physiological; Play; Positioning Attribute; Process; Property; RNA Degradation; RNA Stability; Regulation; Research; Research Personnel; Resolution; Role; Saccharomyces cerevisiae; Saccharomycetales; Structure; System; Techniques; Testing; Time; Work; Yeasts; base; cancer prevention; condensin; driver mutation; exosome; gene repression; histone modification; in vivo; mRNA Stability; mRNA Transcript Degradation; nuclease; stem cells; tomography; transcriptome

Project Summary/Abstract which cell-cycle is regulated, with an emphasis on mechanisms of cell quiescence through chromatin regulation. Eukaryotic cells, from single cell organisms to humans, spend most of their time in quiescence, in which cell exit mitotic cell-cycle in a reversible fashion for long-term survival. Proper control of entry into, maintenance of, and exit from quiescence is essential for cell survival, normal development of organisms, stem cell maintenance and prevention of cancer. However, molecular mechanisms underlying quiescence remains largely unknown. Chromatin regulation plays integral roles in a wide variety of DNA-dependent processes, including transcription, DNA replication, DNA repair, recombination, kinetochore formation, and DNA damage checkpoint response. Therefore, elucidating the mechanisms of chromatin regulation is a necessary prerequisite for understanding how these essential processes are controlled. One of the major challenges in studying chromatin regulation is to elucidate how chromatin regulation affects such a wide variety of processes in the context of important biological contexts, such as cell cycle control and cell differentiation. This is a particularly important challenge, because it was recently determined that mutations in chromatin regulators represent one major class of so called cancer driver mutations, and how these mutations accerelate cancer development remains unknown. Therefore, elucidating the mechanisms of chromatin regulation impacts not only the researchers who study fundamental principle of DNA-dependent processes, but also those who investigate cancer biology and mechanisms of genome stability maintenance. It was recently found that the budding yeast S. cerevisiae can enter quiescent state that share many properties with mammalian quiescence, and a method to purify the quiescent cell was developed. Taking advantage of this system, we have found strong evidence that degradation of specific sets of mRNA is essential for quiescence entry. This strongly suggest the presence of currently unknown mechanism to regulate quiescence entry. We have also found that the high-order structure of chromatin is regulated in quiescence in a way distinct from exponentially growing cells. First, we found that condensin, a highly conserved regulator of chromatin higher-order structure, globally re-localizes during quiescence entry and play key roles in chromatin domain structure in quiescent cells. Secondly, we found that nucleosome arrays are folded into different fashion in quiescent cells. We will take advantage of these recent findings and determine the molecular basis for these observations, which will address a significant gap in our current knowledge about mechanisms underlying quiescence and higher-order chromatin structure.

项目摘要/摘要 哪个细胞周期受调节，重点是通过染色质细胞静止的机理 规定。从单细胞生物到人类的真核细胞将大部分时间花在 静止，其中细胞以可逆的方式出现有丝分裂细胞周期，以实现长期生存。恰当的 控制进入，维持和退出静脉的控制对于细胞存活至关重要，正常 生物的发展，干细胞维持和预防癌症。但是，分子 静脉静止的机制在很大程度上未知。染色质调节起着不可或缺的作用 在多种DNA依赖性过程中，包括转录，DNA复制，DNA修复， 重组，动力学形成和DNA损伤检查点响应。因此，阐明 染色质调节的机制是理解这些方法的必要先决条件 基本过程受到控制。研究染色质调节的主要挑战之一是 阐明染色质调节如何在重要的背景下影响如此广泛的过程 生物环境，例如细胞周期控制和细胞分化。这是一个特别重要的 挑战，因为最近确定染色质调节剂中的突变代表一个 所谓的癌症驱动突变的主要类别，以及这些突变如何加速癌症 发展仍然未知。因此，阐明染色质调节的机制 不仅研究DNA依赖过程基本原则的研究人员，而且还 研究了癌症生物学和基因组稳定性维持的机制。 最近发现，酿酒酵母发芽的酵母菌可以输入共享的静态状态 许多具有哺乳动物静止的特性，以及一种净化静态细胞的方法。 利用该系统，我们发现有力的证据表明特定集的一组 mRNA对于静止进​​入至关重要。这强烈表明目前未知的存在 调节静态进入的机制。我们还发现染色质的高阶结构 以与指数生长的细胞不同的方式进行静止调节。首先，我们发现 冷凝蛋白是一种高度保守的染色质高阶结构的调节剂，在全球范围内重新定位 静止输入并在静态细胞中的染色质结构结构中起关键作用。其次，我们 发现在静态细胞中，核小体阵列被折叠成不同的方式。我们会接受的 这些最新发现的优势，并确定这些观察结果的分子基础，这将 解决我们当前有关静止机制的知识的显着差距 高阶染色质结构。