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在 RNA聚合酶II的启动子近端暂停和转录方向性的确定，关键在过去的几年里，研究人员发现转录的调控步骤对于发育和疾病很重要。研究人员发现，在哺乳动物中，大多数基因的 RNA 聚合酶 (RNAP) II 均在 25-60 nt 处暂停。转录起始位点，一旦提供适当的信号，转录就可以恢复。已发现启动子近端暂停对于基因调控步骤同样重要，甚至可能更为重要目前对于连接知之甚少。 RNAPII 暂停和 ATP 依赖性染色质重塑剂（例如 SWI/SNF）之间的关系，即使已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大多数非编码RNA来自发散或双向转录，其中转录。与 RNAP II 暂停方向性类似，发生在反义方向的编码区上游。转录是一个发育控制的过程，初步数据显示 SWI/SNF 参与了这一过程。这两个过程的调控以及该提案的目标是描述这些过程的分子手段 SWI/SNF 对转录这些相对较新的方面的调节。 SWI/SNF 是癌症中最常见的突变表观遗传因素之一，发生率约为 20% Nicolaides-Baraister 表示，癌症和 SWI/SNF 突变是两种神经系统疾病的分子驱动因素 SWI/SNF 复合体对于多能性和分化也至关重要。作为染色质的主要看门人，它被认为主要参与使 DNA 易于被该提议的前提是SWI/SNF在转录起始复合物中的功能。 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同样重要此外，我们将研究重要的问题。考虑到 SWI/SNF 如何调节 eRNA 的合成，即在增强子区域转录的短 RNA 增强子和启动子的转录具有显着的相似性，通常是双向的，并且使用相同的转录和延伸因子促进启动子和延伸因子之间的长程相互作用。增强子，并在合成其相应的编码 RNA 之前合成。 SWI/SNF 如何影响增强子区域的 RNAPII 暂停和方向性，这可能很重要用于增强子活性。