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，重点是通过染色质调节细胞静止的机制 监管。真核细胞，从单细胞生物到人类，它们的大部分时间都花在 静止期，细胞以可逆的方式退出有丝分裂细胞周期，以获得长期生存。恰如其分 控制进入、维持和退出静止状态是细胞正常生存所必需的 生物体的发展、干细胞的维持和癌症的预防。然而，分子 静默背后的机制在很大程度上仍不清楚。染色质调节起着不可或缺的作用 在广泛的DNA依赖过程中，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，澄清 染色质调节的机制是理解这些 基本过程是受控的。研究染色质调节的主要挑战之一是 阐明染色质调节是如何影响如此广泛的过程的 生物学背景，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器的突变代表一种 主要类别的所谓癌症驱动突变，以及这些突变如何加速癌症 发展情况仍不得而知。因此，阐明染色质调节影响的机制 不仅是研究DNA依赖过程基本原理的研究人员，还有那些 他们研究癌症生物学和基因组稳定性维持的机制。 最近发现，发芽酵母可以进入静止状态，分享 哺乳动物具有静止细胞的许多性质，并发展了一种纯化静止细胞的方法。 利用这一系统，我们发现了强有力的证据表明，特定集合的退化 M RNA是静息进入所必需的。这强烈地表明了目前未知的 调节静止进入的机制。我们还发现染色质的高阶结构 以一种不同于指数增长的细胞的方式在静止状态下进行调节。首先，我们发现， 凝集素是染色质高阶结构的高度保守的调节因子，在 静止期进入并在静止期细胞染色质结构域结构中起关键作用。其次，我们 发现在静止的细胞中，核小体阵列以不同的方式折叠。我们会带上 利用这些最新的发现，并确定这些观察的分子基础，这将 解决我们目前对静止和静止背后的机制的认识中的一个重大差距 高阶染色质结构。