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

基本信息

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
项目类别：
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

项目摘要

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 组件的作用 RNA 转录组转录后加工中的 CHR2/BRM ATP 酶。 CHR2/BRM 是 ATP 酶大开关/蔗糖不可发酵 (SWI/SNF) 染色质重塑复合物的亚基。 SWI/SNF 众所周知，复合物利用 ATP 水解产生的能量来重塑染色质结构。后生动物和酵母 SWI/SNF 复合物也与新生 mRNA 核糖核蛋白复合物相关和长链非编码 RNA (lncRNA)。所有这些研究表明 CHR2 和其他 SWI/SNF 因子发挥作用 RNA 生物学中的非规范角色。 SWI/SNF组件是否以及如何直接参与后处理 RNA 的转录加工尚不清楚。曾经被认为只是DNA之间的一座信使桥梁和蛋白质一样，现在已知 RNA 通过以下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 (RSS) 包含一组新的信息代码，即由专门的蛋白质复合物解释和加工来调节RNA转录、剪接、翻译、本地化和营业额。然而，人们对能够发挥作用的蛋白质/复合物的身份知之甚少。识别特定的靶RNA；以及它们如何促进体内 RSS 的结构重塑。许多RNA 物种还进行转录后 RNA 编辑和/或修饰 (REM)，这甚至增加了更多调节基因表达和生物功能的复杂性。是否以及如何重塑 RSS 和 REM 高等真核生物中，尤其是细胞核中相互之间的交替串扰尚未得到充分研究。 PI 张最近取得了突破性发现，CHR2可以重塑初级前体 microRNA 并抑制其在模式生物拟南芥中的加工。在初步研究中，CHR2 还发现有一个被命名为多细胞器RNA编辑因子8（MORF8）的辅助因子。 MORF8 通常线粒体和质体中的功能参与快速眼动睡眠。重要的是，CHR2 的功能丧失突变体和 MORF8 在 microRNA 途径中具有几乎相同的分子和形态缺陷。在这个因此，张PI希望系统地研究CHR2在转录后转录中的作用。处理各种RNA转录本。具体来说，张PI建议：1）识别CHR2结合 mRNA 和 lncRNA 等，并确定 CHR2 如何改变基因组转录组的 RSS 宽层次； 2)对MORF8在细胞核内进行功能分析；并确定是否以及如何 CHR2控制的RSS重塑和MORF8调节的REM相互作用来控制基因表达式和函数。拟议的研究将揭示非规范但日益重要的作用 RNA 分子转录后加工中的 SWI/SNF 复合物。 SWI/SNF的新功能 RNA 生物学可用于生物技术和制药应用，以解决生理问题由真核生物（包括人类）RNA 加工功能障碍引起的疾病。！