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: 9815856
• 负责人: TOSHIO TSUKIYAMA
• 金额: $ 40.1万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815856
• 关键词: 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; Dimensions; 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; Stem cells; Structure; System; Techniques; Testing; Time; Work; Yeasts; actionable mutation; base; cancer prevention; condensin; exosome; gene repression; histone modification; in vivo; mRNA Stability; mRNA Transcript Degradation; nuclease; 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.

项目概要/摘要 哪个细胞周期受到调节，重点是通过染色质实现细胞静止的机制 规定。真核细胞，从单细胞生物到人类，大部分时间都花在 静止，其中细胞以可逆的方式退出有丝分裂细胞周期以实现长期存活。恰当的 控制进入、维持和退出静止状态对于细胞生存至关重要，正常情况下 生物体的发育、干细胞的维持和癌症的预防。然而，分子 静止背后的机制仍然很大程度上未知。染色质调控发挥着不可或缺的作用 在多种 DNA 依赖性过程中，包括转录、DNA 复制、DNA 修复、 重组、动粒形成和 DNA 损伤检查点反应。因此，阐明 染色质调控机制是理解这些调控机制的必要先决条件 关键过程受到控制。研究染色质调控的主要挑战之一是 阐明染色质调控如何在重要的背景下影响如此广泛的过程 生物学背景，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因子的突变代表了一种 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 发展仍是未知数。因此，阐明染色质调控影响的机制 不仅是研究 DNA 依赖性过程基本原理的研究人员，还包括那些 研究癌症生物学和基因组稳定性维持机制。 最近发现，芽殖酵母酿酒酵母可以进入静止状态，这与 哺乳动物静止的许多特性，并且开发了一种纯化静止细胞的方法。 利用这个系统，我们发现了强有力的证据表明特定组的退化 mRNA 对于进入静止状态至关重要。这强烈表明存在目前未知的 调节静止进入的机制。我们还发现染色质的高级结构 静止状态下的调节方式与指数生长的细胞不同。首先，我们发现 凝缩蛋白是染色质高阶结构的高度保守调节因子，在 进入静止期并在静止细胞的染色质结构域结构中发挥关键作用。其次，我们 发现核小体阵列在静止细胞中以不同的方式折叠。我们将采取 利用这些最近的发现并确定这些观察结果的分子基础，这将 解决我们目前关于静止和潜在机制的知识中的一个重大差距 高阶染色质结构。