Molecular mechanisms and functions of global chromatin control

整体染色质控制的分子机制和功能

• 批准号: 10318937
• 负责人: TOSHIO TSUKIYAMA
• 金额: $ 7.28万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318937
• 关键词: Affect; Animal Model; Biochemistry; Cell Cycle Regulation; Cells; Chromatin; Chromatin Remodeling Factor; DNA; DNA Damage; DNA Repair; DNA biosynthesis; Development; Eukaryotic Cell; Funding; Gene Expression; Genetic Recombination; Genetic Transcription; Genomics; Goals; Malignant Neoplasms; Mitotic Cell Cycle; Modeling; Molecular; Molecular Genetics; Mutation; Nucleosomes; Physical condensation; Process; Regulation; Research Personnel; S phase; Saccharomycetales; Time; Work; Yeasts; driver mutation; genome-wide; in vivo; novel; response

Project Summary/Abstract The long term goal of the proposed study is to determine, at the molecular level, mechanisms and functions of chromatin regulation at a global level. Chromatin regulation profoundly affects a wide variety of DNA-dependent processes, including transcription, DNA replication, recombination, DNA repair, and DNA damage 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 the chromatin field is to elucidate how chromatin is globally reprogrammed during processes like cell fate determination, development and cell-cycle control. 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, yet how these mutations drive cancer remains unknown. Therefore, elucidating the mechanisms of chromatin regulation impacts not only the researchers who study fundamental principles of DNA-dependent processes, but also cancer biologists. We have previously elucidated how chromatin regulation affects transcription, DNA replication, S phase checkpoint and recombination using budding yeast as a model organism. Like most studies in the field, we did our work during the mitotic cell-cycle. However, yeast cells in the wild, like other eukaryotic cells, spend most of their time in quiescence. Quiescence is associated with massive chromatin reprogramming for global condensation. Because the vast majority of work on chromatin regulation has been done during mitotic cell-cycle, we have little idea of how chromatin is regulated during the time cells spend most of their time. In order to understand the whole picture of chromatin regulation in vivo, it is essential to understand mechanisms and functions of chromatin regulation during quiescence. In the next funding period, we will ask the following questions in quiescent state: 1) How is chromatin globally reprogrammed by ATP-dependent chromatin remodeling factors? 2) How are chromatin domains and nucleosome array folding regulated? 3) How is gene expression regulated post-transcriptionally at a global scale? We will use the combination of genomics, molecular genetics, EM, modeling and biochemistry to identify novel mechanisms by which highly conserved chromatin regulators function to massively reprogram chromatin in a genome-wide scale. In the long run, these studies will allow us to compare and integrate the principles of chromatin regulation throughout the mitotic cell-cycle and quiescence, such that we can obtain the full picture of chromatin regulation.

项目摘要/摘要 拟议研究的长期目标是在分子水平上确定机制和 染色质调节在全球层面的功能。染色质调节深刻影响 多种DNA依赖性过程，包括转录，DNA复制，重组，DNA 修复和DNA损伤响应。因此，阐明染色质调节的机制是 了解这些基本过程如何控制的必要先决条件。中的一个 染色质领域的主要挑战是阐明染色质在全球范围内的重新编程 诸如细胞命运确定，发育和细胞周期控制之类的过程。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 代表一类称为癌症驱动器突变的主要类别，但是这些突变如何驱动癌症 仍然未知。因此，阐明染色质调节的机制不仅会影响 研究DNA依赖过程的基本原理的研究人员，也是癌症生物学家。 我们先前已经阐明了染色质调节如何影响转录，DNA复制， S相检查点和重组使用芽酵母作为模型生物。像大多数研究 在有丝分裂细胞周期期间，我们完成了我们的工作。但是，野生酵母细胞像其他 真核细胞，大部分时间都花在静止状态。静止与大规模有关 染色质重编程用于全局凝结。因为绝大多数关于染色质的工作 在有丝分裂细胞周期内进行了调节，我们对如何调节染色质一无所知 在此期间，细胞花费大部分时间。为了了解染色质的整体图片 在体内调节，必须了解染色质调节的机制和功能 静止。在下一个资金期间，我们将在静态状态下提出以下问题：1）如何 由ATP依赖性染色质重塑因子对全球染色质进行了重编程？ 2）如何 调节染色质结构域和核小体阵列折叠？ 3）如何调节基因表达 在全球范围内进行转录？我们将使用基因组学，分子遗传学的组合， EM，建模和生物化学，以确定高度保守染色质的新型机制 调节剂在全基因组范围内的大规模重编除染色质。从长远来看，这些 研究将使我们能够在整个过程中比较和整合染色质调节的原理 有丝分裂细胞周期和静止，使我们可以获得染色质调节的完整图。