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.

项目总结/摘要 细胞周期的调节，强调通过染色质的细胞静止机制 调控真核细胞，从单细胞生物到人类， 静止期，其中细胞以可逆方式退出有丝分裂细胞周期以长期存活。适当 控制进入、维持和退出静止期对于细胞存活、正常生长和存活是必需的。 生物体发育、干细胞维持和癌症预防。然而，分子 静止的潜在机制仍然是未知的。染色质调节起着重要作用 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 染色质调节机制是理解这些细胞如何 关键过程得到控制。研究染色质调控的主要挑战之一是 阐明染色质调控如何影响如此广泛的过程中的背景下，重要的 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 这是一个挑战，因为最近确定染色质调节因子中的突变代表了一个 主要类别的所谓癌症驱动突变，以及这些突变如何与癌症相关 发展仍然未知。因此，阐明染色质调控的机制影响了 不仅是研究DNA依赖过程基本原理的研究人员， 他们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S.酿酒酵母可以进入静止状态， 许多特性与哺乳动物的静止，并开发了一种方法来纯化静止细胞。 利用这一系统，我们发现了强有力的证据，表明特定组的退化， mRNA是进入静止期所必需的。这强烈表明了目前未知的 调节静止进入的机制。我们还发现染色质的高级结构 在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， 凝聚素是一种高度保守的染色质高级结构调节因子， 进入静止期，并在静止期细胞的染色质结构域中发挥关键作用。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 这些最新发现的优势，并确定这些观察的分子基础，这将 解决我们目前对静止机制的认识中的一个重大空白， 高级染色质结构。