Regulation of RNA polymerase II pausing and directionality by ATP-dependent chromatin remodelers

ATP 依赖性染色质重塑剂对 RNA 聚合酶 II 暂停和方向性的调节

基本信息

批准号：
9903395
负责人：
Blaine Bartholomew
金额：
$ 44万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903395
关键词：
AT-Hook Motifs Address Affect Area Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Chromosomes Code Coffin-Siris Syndrome Complex DNA DNA biosynthesis Data Defect Development Disease Elongation Factor Enhancers Epigenetic Process Family Gatekeeping Gene Activation Gene Expression Genes Genetic Transcription Goals Half-Life Knowledge Location Malignant Neoplasms Mammals Maps Mediating Methods Mission Molecular Mus Mutagenesis Mutant Strains Mice Mutate Mutation Nuclear Patients Play Polymerase Positive Transcriptional Elongation Factor B Process Promoter Regions Public Health RNA RNA Polymerase II RNA chemical synthesis Regulation Research Research Personnel Role Running SWI/SNF Family Complex Signal Transduction Stretching System Time Transcript Transcription Elongation Transcription Initiation Transcription Initiation Site Transcription Process Transcriptional Activation Transcriptional Elongation Factors Transcriptional Regulation United States National Institutes of Health Untranslated RNA chromatin remodeling embryonic stem cell histone modification human disease mutant negative elongation factor nervous system disorder pluripotency preference promoter tool transcriptome sequencing

项目摘要

Summary The objective is to study the function of the SWI/SNF ATP-dependent chromatin remodeling complex in promoter proximal pausing of RNA polymerase II and determination of transcriptional directionality, key regulatory steps in transcription important in development and diseases. In the last several years, researchers have found that in mammals most genes have RNA polymerase (RNAP) II paused 25-60 nts from the transcription start site and that transcription can resume once the appropriate signal is provided. Regulation of promoter proximal pausing has been uncovered to be as crucial, or perhaps more, of a regulatory step in gene expression than formation of the preinitiation complex. There is currently very little known about connections between RNAPII pausing and ATP-dependent chromatin remodelers such as SWI/SNF, even though the chromatin structure at the promoter region is known to be an important determining factor in RNAPII pausing. Polymerase pausing is also connected to the occurrence of divergent transcription, another recent finding in transcription. Most non-coding RNA comes from divergent or bidirectional transcription in which transcription occurs upstream of the coding region in the anti-sense direction. Similar to RNAP II pausing the directionality of transcription is a developmentally controlled process. Preliminary data shows SWI/SNF’s involvement in the regulation of both of these processes and the goals of this proposal are to delineate the molecular means of SWI/SNF regulation of these relatively new aspects of transcription. SWI/SNF is one of the most frequently mutated epigenetic factors in cancer, occurring in ~20% of all cancers, and mutations in SWI/SNF are the molecular drivers for two neurological disorders, Nicolaides-Baraister and Coffin-Siris syndromes. The SWI/SNF complex is also crucial for both pluripotency and differentiation. As a master gatekeeper of chromatin, it has been assumed to be primarily involved in making DNA accessible for formation of the transcription initiation complex. The premise of this proposal is that the functions of SWI/SNF in regulation of RNAPII pausing and directionality is as vital for its role in development and human disease as promoting formation of the transcription initiation complex. In addition, we will examine the important question of how SWI/SNF regulates the synthesis of eRNAs, short RNAs transcribed at enhancer regions, given the remarkable similarity with which both enhancers and promoters are transcribed, often bi-directionally, and using the same transcription and elongation factors. eRNAs facilitate long-range interactions between promoters and enhancers, and are synthesized prior to the synthesis of its corresponding coding RNAs. This proposal examines how SWI/SNF influences RNAPII pausing and directionality at enhancer regions, which is likely to be important for enhancer activity.

概括目的是研究SWI/SNF ATP依赖性染色质重塑复合物的功能 RNA聚合酶II的启动子近端暂停并确定转录方向性，钥匙转录的监管步骤在发育和疾病中很重要。在过去的几年中，研究人员已经发现，在哺乳动物中，大多数基因的RNA聚合酶（RNAP）II暂停了25-60 nts 转录起始站点，一旦提供了适当的信号，该转录就可以恢复。调节启动子近端暂停已被发现是基因的调节步骤至关重要的，甚至更大表达比形成前启动复合物。目前对连接鲜为人知在rnapii暂停和依赖ATP的染色质重塑剂（例如SWI/SNF）之间众所周知，启动子区域的染色质结构是RNAPII暂停的重要决定因素。聚合酶暂停也与发散转录的发生有关，这是最近的另一个发现转录。大多数非编码RNA来自不同的转录或双向转录发生在反义方向上的编码区域上游。类似于RNAP II暂停的方向性转录是一个开发的控制过程。初步数据显示了SWI/SNF参与对这两个过程的调节以及该提案的目标是描述分子平均值 SWI/SNF对这些相对较新的转录方面的调节。 SWI/SNF是癌症中最常见的表观遗传因素之一，大约有20％癌症和SWI/SNF中的突变是两种神经系统疾病的分子驱动因素，即尼古德斯 - 巴拉斯特和棺材 - 西里斯综合征。 SWI/SNF复合物对于多能性和分化都至关重要。作为染色质的主看门人，已假定它主要参与使DNA可访问转录起始复合物的形成。该提议的前提是SWI/SNF的功能 RNAPII暂停和方向性的调节对于其在发育和人类疾病中的作用至关重要促进转录起始复合物的形成。此外，我们将研究一个重要的问题关于SWI/SNF如何调节ERNAS的合成，鉴于该区域的简短RNA在增强剂区域转录。具有相似之处的相似性，通常双向抄录，并使用这些相似之处相同的转录和伸长因子。 ERNAS促进了启动子与增强剂，并在合成其相应的编码RNA之前合成。该提案考试 SWI/SNF如何影响增强子区域的RNAPII暂停和方向性，这很可能很重要用于增强剂活动。