Gene-specific transcriptional silencing directed by dephosphorylation of RNAP II

RNAP II 去磷酸化指导的基因特异性转录沉默

基本信息

批准号：
8703729
负责人：
Yan Jessie Zhang
金额：
$ 27.28万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703729
关键词：
Address Affect Alzheimer&apos s Disease Area Binding Biological Biological Assay C-terminal Cell Death Cells Chemicals Code Complex DNA Polymerase II Defect Degenerative Disorder Development Dominant-Negative Mutation Drug Targeting Enzymes Essential Genes Eukaryotic Cell Gene Expression Gene Silencing Genes Genetic Transcription Goals Human Kinetics Laboratories Lead Malignant Neoplasms Messenger RNA Modeling Modification Molecular Molecular Target Natural regeneration Neurodegenerative Disorders Neuronal Differentiation Neurons Outcome Patients Pattern Peptides Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Post-Translational Protein Processing Process Protein Dephosphorylation Proteins RNA RNA Polymerase II Recruitment Activity Regulation Research Specificity Stem cells Structure Testing Time Transcription Process Transcriptional Regulation Variant base biophysical techniques carboxy-terminal domain phosphatase cell type combinatorial enzyme mechanism genetic regulatory protein inhibitor/antagonist neurogenesis neuron development prevent promoter protein complex public health relevance stem cell differentiation structural biology tool transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The transcription process in eukaryotic cells is controlled by the C-terminal domain of RNA polymerase II through its post-translational modification states. However enzymes that recognize the same phosphorylation site in CTD can lead to different transcriptional outcomes. To address the central question that how gene-specific regulation was achieved by CTD regulatory enzymes; we investigate the structure function mechanism of Scp, a human CTD Ser5 phosphatase that functions as a co-repressor for neuronal gene expression. By comparing gene-specific CTD phosphatase Scp, to general-transcription CTD phosphatase Ssu72, we will test two different yet not mutually exclusive hypotheses to explain the differentiated transcription outcomes: molecular targeting and gene-specific CTD code. Finally, we will identify neuronal genes that are subject to Scp regulation and develop chemical tools to investigate the gene expression cascade during neurogenesis. The research breaks new ground in understanding CTD-directed transcription regulation. The chemical compounds developed in this study will become powerful tools to understand the biological mechanism of neuronal stem cell differentiation. Finally, the study of Scp-directed gene silencing in various cell types pave the way to establish if Scp can be a valid drug target for neurodegenerative diseases such as Alzheimer's.

描述（由申请人提供）：真核细胞中的转录过程由RNA聚合酶II的C末端结构域通过其翻译后修饰状态控制。但是，识别CTD中相同磷酸化位点的酶会导致不同的转录结果。为了解决一个核心问题，即CTD调节酶如何实现基因特异性调节；我们研究了SCP的结构功能机理，SCP是一种人CTD SER5磷酸酶，充当神经元基因表达的共抑制剂。通过将基因特异性CTD磷酸酶SCP与一般转录CTD磷酸酶SSU72进行比较，我们将测试两个不同但非相互排斥的假设，以解释分化的转录结果：分子靶向和基因特异性CTD代码。最后，我们将确定受SCP调节的神经元基因，并开发化学工具以研究神经发生过程中基因表达级联反应。这项研究打破了理解CTD定向转录调控的新基础。这项研究中开发的化合物将成为了解神经元干细胞分化的生物学机制的强大工具。最后，对各种细胞类型中SCP定向基因沉默的研究为确定SCP是否可以成为神经退行性疾病（例如阿尔茨海默氏病）的有效药物靶标。