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Transcriptome regulation during mitosis

有丝分裂期间的转录组调控

基本信息

批准号：
10359186
负责人：
Michael Demian Blower
金额：
$ 33.99万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359186
关键词：
Affect Aneuploidy Binding Cancer Etiology Cell Cycle Cell Nucleus Cell division Cells Centromere Chromatin Chromosome Condensation Chromosome Segregation Chromosomes Complex Congenital Abnormality Cytoplasm Development Down-Regulation Ensure Excision Exhibits Failure Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Transcription Genomic Segment Goals Inherited Interphase Kinetochores Lead Malignant Neoplasms Mediating Meiosis Messenger RNA Microtubules Mitosis Mitotic Mitotic Chromosome Mitotic spindle Molecular Monitor Nuclear Nuclear Envelope Nuclear RNA Pattern Phosphorylation Play Process Prophase Proteins RNA RNA Binding RNA analysis Recycling Regulation Role Signaling Molecule Sister Chromatid Site Spontaneous abortion Testing Time Transcriptional Regulation Untranslated RNA Work cohesin daughter cell insight novel programs recruit transcriptome tumor progression

项目摘要

Project Summary Accurate chromosome segregation during mitosis and meiosis is critical for viability and development. Errors in chromosome segregation lead to aneuploidy, which is closely correlated with cancer. In order to ensure accurate chromosome segregation duplicated sister chromatids must be dramatically condensed and individualized upon entry into mitosis. Accurate chromosome distribution during mitosis depends on the interaction of duplicated sister chromatids with the microtubules of the mitotic spindle. Each chromosome contains one centromere that serves as the site for the formation of the kinetochore. At nuclear envelope breakdown, proteins important for kinetochore:microtubule (K:MT) attachment and signaling molecules that monitor K:MT attachment are recruited to the kinetochore. Successful completion of cell division requires the coordinated regulation of centromere/kinetochore assembly, kinetochore:microtubule attachment and chromosome condensation. Decades of work have identified hundreds of proteins that regulate various aspects of mitosis. However, very little is known about regulation of the transcriptome during mitosis. Recent work has demonstrated that remodeling of the transcriptome plays an important role in mitotic regulation. This proposal will study two fundamental aspects of transcriptome remodeling during mitosis. First, during mitosis, the majority of nuclear transcription is blocked, however, centromeres escape transcriptional down-regulation. Surprisingly, very little is known about the mechanism of transcriptional inhibition during mitosis or how disruption of mitotic transcriptional inhibition impacts the fidelity of chromosome segregation. It is also unknown if the process of mitotic transcriptional inhibition contributes to changing gene expression patterns. Second, during interphase hundreds to thousands of RNAs are retained in the nucleus where they bind to chromatin and regulate nuclear organization and gene expression. During mitosis many nuclear RNAs are released from chromatin, yet little is known about the mechanism of RNA removal from chromatin during mitosis. Additionally, it is unknown how disruption of RNA release from chromatin impacts the process of chromosome segregation or gene expression following mitosis. Our work will investigate how the transcriptome is remodeled during mitosis and how this contributes to accurate chromosome segregation.

项目概要有丝分裂和减数分裂过程中准确的染色体分离对于活力和减数分裂至关重要发展。染色体分离错误导致非整倍体，这与染色体分离密切相关患有癌症。为了确保精确的染色体分离重复的姐妹染色单体在进入有丝分裂时必须急剧浓缩和个体化。准确的有丝分裂期间的染色体分布取决于复制姐妹的相互作用染色单体与有丝分裂纺锤体的微管。每条染色体包含一条着丝粒是着丝粒形成的场所。在核膜处分解，对动粒重要的蛋白质：微管 (K:MT) 附着和信号传导监测 K:MT 附着的分子被招募到着丝粒。成功的细胞分裂的完成需要着丝粒/动粒的协调调节组装、动粒：微管附着和染色体凝结。数十年的工作已经鉴定出数百种调节各个方面的蛋白质有丝分裂。然而，人们对有丝分裂过程中转录组的调控知之甚少。最近的工作表明转录组的重塑在有丝分裂调节。该提案将研究转录组重塑的两个基本方面有丝分裂期间。首先，在有丝分裂期间，大部分核转录被阻断，然而，着丝粒逃避转录下调。令人惊讶的是，人们对它知之甚少有丝分裂过程中转录抑制的机制或如何破坏有丝分裂转录抑制影响染色体分离的保真度。也未知该过程是否有丝分裂转录抑制有助于改变基因表达模式。第二，在分裂间期，成百上千的 RNA 被保留在细胞核中，并在那里结合染色质并调节核组织和基因表达。有丝分裂期间许多核RNA从染色质中释放出来，但人们对RNA的机制知之甚少有丝分裂期间从染色质中去除。此外，尚不清楚 RNA 是如何被破坏的。染色质的释放影响染色体分离或基因表达的过程有丝分裂后。我们的工作将研究转录组在有丝分裂过程中如何重塑以及这如何有助于准确的染色体分离。