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: 10645489
• 负责人: TOSHIO TSUKIYAMA
• 金额: $ 74.06万
• 依托单位: FRED HUTCHINSON CANCER 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645489
• 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.

项目概要/摘要 拟议研究的长期目标是在分子水平上确定机制和 全球水平染色质调控的功能。染色质调控深刻影响着广泛的 各种 DNA 依赖性过程，包括转录、DNA 复制、重组、DNA 修复和 DNA 损伤反应。因此，阐明染色质调控机制是一个重要的课题。 了解如何控制这些基本过程的必要先决条件。中的一个 染色质领域的主要挑战是阐明染色质如何在整个过程中进行全局重编程 细胞命运决定、发育和细胞周期控制等过程。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 代表一类主要的所谓癌症驱动突变，但这些突变如何驱动癌症 仍然未知。因此，阐明染色质调控机制不仅影响 研究 DNA 依赖性过程基本原理的研究人员，也是癌症生物学家。 我们之前已经阐明了染色质调控如何影响转录、DNA 复制、 使用芽殖酵母作为模型生物的 S 期检查点和重组。就像大多数研究一样 在该领域，我们在有丝分裂细胞周期期间进行了工作。然而，野生酵母细胞与其他细胞一样 真核细胞大部分时间处于静止状态。静止与大量的 染色质重编程以实现全局凝聚。因为绝大多数工作都在染色质上 调节是在有丝分裂细胞周期期间完成的，我们对染色质是如何调节的知之甚少 在此期间，细胞度过了大部分时间。为了了解染色质的全貌 体内调节，了解染色质调节的机制和功能至关重要 静止。在下一个资助期间，我们将在静止状态下提出以下问题：1）如何？ 染色质通过 ATP 依赖性染色质重塑因子进行全局重编程？ 2) 怎么样 染色质结构域和核小体阵列折叠受到调节吗？ 3）基因表达是如何调控的 在全球范围内转录后？我们将结合基因组学、分子遗传学、 EM、建模和生物化学，以确定高度保守的染色质的新机制 调节因子的作用是在全基因组范围内大规模重新编程染色质。从长远来看，这些 研究将使我们能够比较和整合整个染色质调控的原理 有丝分裂细胞周期和静止，这样我们就可以获得染色质调控的全貌。