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Chromatin Dynamics in the Cell Cycle

细胞周期中的染色质动力学

基本信息

批准号：
10228361
负责人：
Lindsey Renee Pack
金额：
$ 1.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228361
关键词：
ATAC-seq Acetylation Address Affect Aging Biological Assay Biosensor CCNE1 gene Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Chemicals Chromatin Chromatin Remodeling Factor Complex Coupling Cues Cyclin D1 Cyclin-Dependent Kinases DNA Packaging Data Defect Deposition Disease EZH2 gene Enzyme Activation Epithelial Cells Excision Gene Expression Genes Genetic Transcription Global Change Goals High-Throughput Nucleotide Sequencing Histone H3 Histone H4 Histones Homeostasis Hour Human Individual Kinetics Lead Lysine MCF10A cells Maintenance Malignant Neoplasms Measurement Methods Methylation Microscopy Mitogen-Activated Protein Kinases Mitogens Mitosis Modification Pathway interactions Probability Proliferating Proteins Regulation Research Role Signal Pathway Signal Transduction Site Techniques Testing Time Tissues Transcriptional Regulation Transposase Work cdc Genes chromatin immunoprecipitation chromatin modification endonuclease experience genome-wide histone modification imaging approach interest knock-down live cell imaging new therapeutic target novel promoter recruit sensor targeted treatment therapeutic target time use training opportunity

项目摘要

Project Summary/Abstract The ability of cells to robustly enter and exit quiescence is essential for tissue homeostasis, and defects in the transition between proliferation and quiescence lead to diseases of excess proliferation (cancer) or cell loss (aging and degeneration). Critical to this transition are gene expression changes regulated by well understood signaling pathways. In addition to transcriptional changes, chromatin modification and accessibility is regulated between quiescent and proliferating cells, and the functions of chromatin modifiers have been shown to disrupt these transitions. However, the mechanisms by which chromatin affects the ability of cells to transition between quiescence and proliferation are unknown. The goal of this proposal is to characterize global and gene-specific chromatin modification and accessibility changes, and define how chromatin regulation affects the ability of cells to transition in and out of quiescence. The central hypothesis is that distinct chromatin modifications regulate the entry, exit, and maintenance of quiescence through control of both chromatin accessibility and site-specific transcriptional control of critical cell cycle genes. This hypothesis will be tested in three specific aims: (1) Define the functional role of global changes in chromatin modifications in proliferating and quiescent cells. (2) Identify and induce site-specific chromatin modification changes at the promoters of critical cell cycle regulated genes. (3) Determine changes in chromatin accessibility in quiescent and proliferating cells. Global and site-specific chromatin modifications changes will be identified in quiescent and proliferating human epithelial cells. The role of these changes in cell cycle regulation will be determined by disrupting the chromatin regulators responsible for the deposition and removal of the modifications of interest, and using time lapse microscopy to image live-cell sensors for activities critical to cell cycle progression. This quantitative method will identify aspects of the cell cycle, which are perturbed by changes in chromatin modification, including probability of quiescence and time to cell cycle re-entry. Moreover, changes in chromatin accessibility in this critical transition will be identified, and the role of modifications in regulating chromatin accessibility will be evaluated. This work will contribute to the field by defining a novel pathway, chromatin dynamics, which functions to regulate cell cycle entry and exit. Furthermore, the proposed work will advance the understanding of the mechanisms by which chromatin modifiers control the establishment and maintenance of chromatin marks. Finally, the proposed work will offer new targets for therapeutic treatment of diseases of tissue homeostasis, including cancer.

项目总结/摘要细胞稳健地进入和退出静止期的能力对于组织稳态是必不可少的，并且在细胞内的缺陷是不可或缺的。增殖和静止之间的过渡导致过度增殖的疾病（癌症）或细胞损失（老化和退化）。这种转变的关键是基因表达的变化，信号通路除了转录变化，染色质修饰和可及性也受到调控之间的静止和增殖细胞，染色质修饰剂的功能已被证明是破坏这些过渡。然而，染色质影响细胞在细胞核和细胞核之间转换的能力的机制，静止和增殖是未知的。这项提案的目标是表征全球和基因特异性染色质修饰和可及性变化，并定义染色质调节如何影响细胞进入和脱离静止状态的能力。中心假设是不同的染色质修饰调节细胞的进入、退出和维持。通过控制关键细胞染色质可接近性和位点特异性转录控制来实现静止周期基因将在三个具体目标中检验这一假设： (1)定义增殖和静止细胞中染色质修饰的整体变化的功能作用。 (2)识别并诱导关键细胞周期启动子处的位点特异性染色质修饰变化调控基因 (3)测定静止期和增殖期细胞中染色质可及性的变化。将在静止期和增殖期的人类细胞中鉴定出全局和位点特异性染色质修饰变化。上皮细胞这些变化在细胞周期调控中的作用将通过破坏染色质来确定负责沉积和移除感兴趣的修改的监管机构，并使用时间间隔显微镜成像活细胞传感器的活动至关重要的细胞周期进程。这种定量方法将确定细胞周期的各个方面，这些方面受到染色质修饰变化的干扰，包括概率和细胞周期重新进入的时间。此外，在这一关键的染色质可及性的变化，将确定转换，并将评估修饰在调节染色质可及性中的作用。这项工作将有助于该领域的定义一个新的途径，染色质动力学，其功能是调节细胞周期的进入和退出此外，拟议的工作将通过以下方式增进对这些机制的理解：所述染色质修饰剂控制染色质标记的建立和维持。最后，建议这项工作将为包括癌症在内的组织稳态疾病的治疗提供新的靶点。