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Analysis of chromatin-RNA interactions during the cell cycle.

细胞周期中染色质-RNA 相互作用的分析。

基本信息

批准号：
10593100
负责人：
Michael Demian Blower
金额：
$ 33万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-16 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593100
关键词：
ATPase Domain Affect Architecture Binding Binding Proteins Biochemical Biological Cell Cycle Cell Line Cell Nucleus Cell division Cells Chromatin Chromatin Loop Chromatin Structure Chromosome Condensation Chromosome Segregation Chromosome Structures Chromosomes Complex DNA DNA Polymerase II Development Enzymes Euchromatin Event Excision Gene Expression Gene Expression Regulation Genetic Genetic Epistasis Genetic Transcription Genome Genome Stability Genomic approach Genomics Goals Heterochromatin Histones Human Human Development Image In Vitro Interphase Interphase Chromosome Knowledge Link Malignant Neoplasms Mediating Messenger RNA Mitosis Mitotic Mitotic Chromosome Molecular Mus Mutation Neurodevelopmental Disorder Nuclear Nuclear Protein Nuclear Structure Nucleic Acid Biochemistry Nucleic Acids Pathway Analysis Pathway interactions Phenotype Phosphorylation Physical condensation Preparation Process Prophase Proteins RNA RNA Binding RNA Splicing Regulation Sister Chromatid Structure Surface Time Transcriptional Activation Transcriptional Regulation Untranslated RNA Work cancer cell chromatin remodeling cohesin condensin de novo mutation design experimental study genetic analysis genetic information genetically modified cells human error insight non-histone protein programs protein oligomer reconstitution segregation telophase transcription factor

项目摘要

DNA is packaged by histone proteins into chromatin in order to fit into the nucleus of a cell. Globally, chromatin can be separated into open, transcriptionally active and closed, transcriptionally silent compartments. Many different nonhistone, chromatin-binding proteins contribute to global chromatin structure. Chromatin remodeling enzymes, transcription factors, and transcription-associated RNAs are important for decondensing transcriptionally active portions of the genome. Heterochromatin proteins and associated noncoding RNAs are important for condensation of the transcriptionally inactive portions of the genome. Changes in chromatin organization and compaction are critical for cell state changes during development and chromosome segregation during mitosis. Chromosome structure changes dramatically at the beginning of mitosis as chromosomes compact and individualize in preparation for segregation. As cells enter into mitosis all of the structure present in the interphase nucleus is erased. Erasure of interphase nuclear structure is correlated with the stepwise removal of the Cohesin complex. Chromosome condensation and individualization are accomplished by the combined action of the Condensin complexes and Topoisomeriase IIα. Interestingly, dramatic changes in chromosome structure are temporally correlated with suppression of transcription. At the end of mitosis chromosomes cluster and decondense to reform a single interphase nucleus. Chromosome decondensation and clustering is accomplished by the rebinding of many different proteins that are removed from chromatin during mitosis and is temporally correlated with the resumption of nuclear transcription. While changes in chromatin structure during mitosis are correlated with changes in nuclear transcriptional activity, little is known about how the two processes are linked. We have recently discovered that prophase removal of the Cohesin complex form chromosomes is critical for silencing mitotic transcription and that removal of chromatin-bound RNAs from chromosomes during mitosis is mediated by phosphorylation of SAF-A. The identification of molecular pathways linking changes in chromosome structure to changes in transcriptional activity presents an opportunity to understand how these events are linked. In this proposal we will reconstitute the biochemistry of nucleic acid interactions mediated by SAF-A to provide a picture of how this abundant protein controls chromosome structure. We will then examine how removal of SAF-A from chromatin promotes chromosome condensation during prophase. We will then examine how rebinding of SAF- A to chromatin at the end of mitosis promotes nuclear reformation and transcriptional activation. Collectively, the experiments outlined in this proposal will provide new insight into changes in chromatin-RNA interactions that control chromatin structure and how these changes contribute to accurate chromosome segregation and transcriptional regulation.

DNA被组蛋白包装成染色质，以适应细胞核。在全球范围内，可以分为开放的转录活性区室和封闭的转录沉默区室。许多不同的非组蛋白，染色质结合蛋白有助于整体染色质结构。染色质重塑酶、转录因子和转录相关的RNA对于解压缩是重要的。基因组的转录活性部分。异染色质蛋白和相关的非编码RNA是对于基因组的转录非活性部分的浓缩是重要的。染色质变化组织和压实对于发育期间的细胞状态变化至关重要，在有丝分裂期间分离。在有丝分裂开始时，染色体结构发生显著变化，为种族隔离做准备。当细胞进入有丝分裂时，间期核被擦除。相间核结构的擦除与逐步去除有关内聚素复合体的一部分染色体的浓缩和个体化是通过组合缩合复合物和拓扑异构酶IIα的作用。有趣的是，结构在时间上与转录抑制相关。在有丝分裂染色体的末端群集和解密集以改革单个相间核。染色体解凝聚和成簇是通过有丝分裂过程中从染色质中去除的许多不同蛋白质的重新结合来完成，在时间上与核转录的恢复相关。虽然有丝分裂过程中染色质结构的变化与细胞核的变化有关，尽管这两个过程都具有转录活性，但人们对这两个过程如何联系知之甚少。我们最近发现在分裂前期去除染色体形式的粘连蛋白复合物对于有丝分裂转录的沉默是至关重要的在有丝分裂过程中，染色质结合RNA从染色体上的去除是由磷酸化介导的的SAF-A。染色体结构变化与细胞周期变化之间的分子通路的鉴定，转录活性提供了一个机会，以了解这些事件是如何联系在一起的。在本提案中，我们将重建由SAF-A介导的核酸相互作用的生物化学，以提供一个如何这种丰富的蛋白质控制染色体结构。然后，我们将研究如何删除SAF-A从染色质在前期促进染色体凝聚。然后，我们将研究如何重新绑定SAF- A在有丝分裂末期与染色质结合，促进核重组和转录激活.总的来说，这项计划中概述的实验将为研究染色质-RNA相互作用的变化提供新的视角控制染色质结构以及这些变化如何有助于准确的染色体分离，转录调控