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

• 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
• 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' 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

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。然而，识别CTD中相同磷酸化位点的酶可导致不同的转录结果。为了解决如何通过CTD调节酶实现基因特异性调节的核心问题，我们研究了Scp的结构和功能机制，Scp是一种人类CTD Ser5磷酸酶，其功能是神经元基因表达的共阻遏物。通过比较基因特异性CTD磷酸酶Scp和通用转录CTD磷酸酶Ssu72，我们将测试两种不同但不相互排斥的假设来解释差异化的转录结果：分子靶向和基因特异性CTD代码。最后，我们将确定受Scp调控的神经元基因，并开发化学工具来研究神经发生过程中的基因表达级联。这项研究在理解CTD指导的转录调控方面开辟了新天地。本研究开发的化合物将成为了解神经干细胞分化生物学机制的有力工具。最后，在各种细胞类型中Scp指导的基因沉默的研究为确定Scp是否可以成为神经退行性疾病如阿尔茨海默氏症的有效药物靶标铺平了道路。