Roles of SWI/SNF complexes in posttranscriptional processing of RNA

SWI/SNF 复合物在 RNA 转录后加工中的作用

• 批准号: 9905546
• 负责人: Xiuren Zhang
• 金额: $ 28.94万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-02 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905546
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Address; Agriculture; Animal Model; Arabidopsis; Architecture; Binding; Biogenesis; Biological Assay; Biological Process; Biology; Biotechnology; Cell Nucleus; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Code; Complex; DNA; Defect; Disease; Eukaryota; Functional disorder; Gene Expression; Genetic Transcription; Goals; Health; Human; Immunoprecipitation; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Microprocessor; Mitochondria; Modification; Molecular; Morphology; Multiplexed Analysis of Projections by Sequencing; Mutagenesis; Mutation; Names; Nucleosomes; Orthologous Gene; Pathway interactions; Pharmacologic Substance; Phenocopy; Phenotype; Physiological; Plastids; Play; Post-Transcriptional RNA Processing; Process; Production; Proteins; Proteomics; RNA; RNA Editing; RNA Processing; RNA Splicing; Research; Ribonucleoproteins; Role; SWI2/SNF2; Secure; Series; Small RNA; Structure; Sucrose; Testing; Therapeutic; Transcript; Translations; Untranslated RNA; Variant; Yeasts; chromatin remodeling; cofactor; dimethyl sulfide; gene function; genome-wide; human disease; improved; in vivo; knock-down; loss of function; mRNA Precursor; messenger ribonucleoprotein; mutant; novel; pri-miRNA; protein complex; trait; transcriptome; transcriptome sequencing

The primary goal of the proposed research is to determine the roles of SWI/SNF component CHR2/BRM ATPase in posttranscriptional processing of RNA transcriptome. CHR2/BRM is the ATPase subunit of the large SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes. SWI/SNF complexes are best known to remodel chromatin structures using energy derived from ATP hydrolysis. Metazoan and yeast SWI/SNF complexes also associate with nascent mRNA ribonucleoprotein complexes and long-noncoding RNAs (lncRNAs). All these studies suggest that CHR2 and other SWI/SNF factors play non-canonical roles in RNA biology. Whether and how SWI/SNF components directly participate in post- transcriptional processing of RNA are unknown. Once thought to be only a messenger bridge between DNA and proteins, RNA is now known to influence many aspects of biology through activities that are attributable to its secondary structures. In fact, RNA secondary structures (RSS) contain a new set of information code that is interpreted and processed by specialized protein complexes to regulate RNA transcription, splicing, translation, localization and turnover. However, little is known about the identities of the proteins/complexes that can recognize specific target RNAs; and how they promote the structural remodeling of RSS in vivo. Many RNA species also undertake posttranscriptional RNA editing and /or modifications (REMs), which even add more complexity to regulate gene expression and biological functions. Whether and how RSS remodeling and REM alternation crosstalk with each other in higher eukaryotes, especially in the nucleus, is underexplored. The PI Zhang has recently made a groundbreaking discovery that CHR2 could remodel primary precursors of microRNAs and inhibit their processing in the model organism Arabidopsis. In the preliminary study, CHR2 was also found to have a cofactor named as multiple organellar RNA editing factor 8 (MORF8). MORF8 typically functions in mitochondria and plastids to participate in REMs. Importantly, loss-of-function mutants of CHR2 and MORF8 share nearly identical molecular and morphological defects in the microRNA pathway. In this setting, the PI Zhang would like to systematically investigate the roles of CHR2 in posttranscriptional processing of various RNA transcripts. Specifically, The PI Zhang proposes to: 1) identify the CHR2-bound mRNAs and lncRNAs among others and determine how CHR2 alters the RSS of transcriptome at the genome- wide level; and 2) conduct functional analysis of MORF8 in the nucleus; and determine whether and how CHR2-controlled RSS remodeling and MORF8-regulated REMs interplay with each other to control gene expression and functions. The proposed study will reveal the non-canonical but increasingly important roles of SWI/SNF complexes in posttranscriptional processing of RNA molecules. The new functions of SWI/SNF in RNA biology may be exploited in biotechnological and pharmaceutical applications to address physiological disorders that arise from dysfunctions of RNA processing in eukaryotes including human. !

拟议研究的主要目标是确定SWI/SNF组件的角色 ChR2/BRM-ATPase在RNA转录组转录后加工中的作用ChR2/BRM是ATPase 大开关/蔗糖不可发酵(SWI/SNF)染色质重塑复合体的亚单位。SWI/SNF 最广为人知的是，络合物使用来自ATP水解的能量来重塑染色质结构。 后生动物和酵母SWI/SNF复合体也与新生的mRNA核糖核蛋白复合体有关 和长非编码RNA(LncRNAs)。所有这些研究表明，ChR2和其他SWI/SNF因子在其中起作用 核糖核酸生物学中的非规范作用。SWI/SNF组件是否以及如何直接参与后 RNA的转录加工是未知的。曾经被认为只是DNA之间的信使桥梁 和蛋白质，现在已知RNA通过可归因于以下几个方面的活动影响生物学的许多方面 它的二级结构。事实上，RNA二级结构(RS)包含一组新信息编码， 由专门的蛋白质复合体解释和处理，以调节RNA的转录、剪接、翻译， 本地化和流动化。然而，人们对这些蛋白质/复合体的特性知之甚少 识别特定的靶RNA；以及它们如何促进体内RSS的结构重塑。很多核糖核酸 物种还进行转录后RNA编辑和/或修饰(REMS)，这甚至会增加更多 调节基因表达和生物功能的复杂性。RSS是否以及如何重塑和REM 在高等真核生物中，特别是在细胞核中，相互之间的交替串扰还没有得到充分的研究。《少年派》 张最近有了一个突破性的发现，即ChR2可能会重塑 并在模式生物拟南芥中抑制其加工。在初步研究中，ChR2是 还发现了一种名为多细胞器RNA编辑因子8(MORF8)的辅因子。MORF8通常 线粒体和叶绿体中参与REMS的功能。重要的是，ChR2的功能缺失突变体 与MORF8在microRNA途径中具有几乎相同的分子和形态缺陷。在这 在这样的背景下，皮张想要系统地研究ChR2在转录后的作用 各种RNA转录本的处理。具体地说，皮张建议：1)识别ChR2结合 MRNAs和lncRNAs等，并确定ChR2如何改变基因组转录组的RSS- 2)在细胞核内进行MORF8的功能分析，并确定是否以及如何 ChR2调控的RSS重塑和MORF8调控的RMS相互作用控制基因 表达式和函数。拟议中的研究将揭示非规范但日益重要的角色 SWI/SNF复合体在RNA分子转录后加工中的作用SWI/SNF的新功能 RNA生物学可以在生物技术和制药应用中被利用来解决生理 在包括人类在内的真核生物中，由于核糖核酸处理功能障碍而引起的疾病。 好了！