Non-coding RNAs in Transcription and Chromatin Architecture

转录和染色质结构中的非编码 RNA

基本信息

批准号：
8851981
负责人：
RAMIN SHIEKHATTAR
金额：
$ 27.55万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851981
关键词：
Affect Architecture Benign Biological Cell Nucleus Chromatin Chromatin Loop Chromatin Structure Code Cognitive Complex Data Development Developmental Biology Enhancers Epigenetic Process Exhibits FG Syndrome Functional RNA Gene Expression Genes Genetic Transcription Health Histone H3 Histones Human Human Development Human Genome In Vitro Lead Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Mus Mutation Nuclear Open Reading Frames Phosphotransferases Proteins RNA RNA Recognition Motif RNA Sequences Recurrence Role Serine Site Smooth Muscle Tumor Specific qualifier value Specificity Structure Syndrome Testing Transcript Transcriptional Activation Transcriptional Regulation Uterine Fibroids Work X Inactivation base cell type design disease-causing mutation embryonic stem cell genome-wide human disease imprint in vivo insight interest pluripotency public health relevance research study tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Project Summary We have recently identified a class of long ncRNA termed ncRNA-activating (ncRNA-a), which can activate the expression of neighboring protein-coding genes at long distances. Our current data suggest that ncRNA-a function by associating with the co-activator complex, Mediator, to promote DNA looping. The association between ncRNA-a and the Mediator complex will be investigated to understand how specificity for target selection is achieved and to pinpoint the contribution of RNA to transcriptional activation. The three Aims are designed to provide a thorough molecular understanding of the activating ncRNAs and their association with the Mediator complex. Aim1 describes experiments that examine the molecular basis for ncRNA-a nuclear localization and transcriptional activation. Aim 2 describes experiments to delineate the molecular basis of ncRNA-a and the Mediator complex interaction. We will determine whether ncRNA-a is critical for the recruitment of Mediator to its target sites and perform structure/function experiments to assess the importance of ncRNA-a/Mediator interaction in transcriptional activation. Aim3 will assess the molecular basis by which ncRNA-a activates the CDK8 kinase activity. Importantly, recurrent mutations in Med12 subunit of Mediator complex, which is critical for kinase activity, result in development of multiple human cognitive syndromes and a benign smooth muscle neoplasm. Therefore, we will test the hypothesis that such mutations affect the kinase activity of Mediator by disrupting its association with the ncRNA-a.

描述（由申请人提供）：项目摘要我们最近发现了一类长 ncRNA，称为 ncRNA 激活 (ncRNA-a)，它可以远距离激活邻近蛋白质编码基因的表达。我们目前的数据表明，ncRNA-a 通过与共激活剂复合物介体结合来发挥作用，以促进 DNA 循环。我们将研究 ncRNA-a 和介体复合物之间的关联，以了解如何实现靶标选择的特异性，并查明 RNA 对转录激活的贡献。这三个目标旨在提供对激活 ncRNA 及其与介体复合物关联的全面分子理解。 Aim1 描述了检查 ncRNA-a 核定位和转录激活分子基础的实验。目标 2 描述了描述 ncRNA-a 和介体复合物相互作用的分子基础的实验。我们将确定 ncRNA-a 是否对于将介体招募到其靶位点至关重要，并进行结构/功能实验以评估 ncRNA-a/介体相互作用在转录激活中的重要性。 Aim3 将评估 ncRNA-a 激活 CDK8 激酶活性的分子基础。重要的是，介导复合物的 Med12 亚基（对激酶活性至关重要）的反复突变会导致多种人类认知综合征和良性平滑肌肿瘤的发生。因此，我们将检验这样的假设：此类突变通过破坏 Mediator 的关联来影响 Mediator 的激酶活性与 ncRNA-a。