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组件的作用 RNA转录组的转录后处理中的CHR2/BRM ATPase。 CHR2/BRM是ATPase 大开关/蔗糖不可发酵（SWI/SNF）染色质复合物的亚基。 SWI/SNF 众所周知，使用来自ATP水解的能量重塑染色质结构。 内唑和酵母SWI/SNF复合物也与新生的mRNA核糖核蛋白复合物相关联 和长期编码的RNA（lncrnas）。所有这些研究表明CHR2和其他SWI/SNF因素播放 RNA生物学中的非经典作用。 SWI/SNF组件是否以及如何直接参与后 RNA的转录处理未知。曾经被认为只是DNA之间的一座信 和蛋白质，RNA现在众所周知会通过可归因于生物学的许多方面 其二级结构。实际上，RNA二级结构（RSS）包含一组新的信息代码 由专门的蛋白质复合物解释和处理，以调节RNA转录，剪接，翻译， 本地化和营业额。但是，关于可以的蛋白质/复合物的身份知之甚少 识别特定的目标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 /或修改（REMS），甚至增加了更多 调节基因表达和生物学功能的复杂性。 RSS是否以及如何进行重塑和REM 在较高的真核生物中，尤其是在核中，彼此之间的交替串扰彼此没有被逐渐解散。 pi 张最近发现了Chr2可以重塑主要前体的发现 microRNA并抑制其在模型生物拟南芥中的加工。在初步研究中，Chr2是 还发现有一个辅助因子称为多个细胞器RNA编辑因子8（MORF8）。 MORF8通常 线粒体和质体的功能参与REM。重要的是，CHR2的功能丧失突变体 MORF8在microRNA途径中具有几乎相同的分子和形态缺陷。在这个 设置，Pi Zhang希望系统地研究CHR2在转录后的作用 处理各种RNA转录本。具体而言，pi张提出：1）识别chr2结合 mRNA和LNCRNA等人确定CHR2如何改变基因组的转录组RSS 宽水； 2）对核中MORF8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REMS相互作用以控制基因 表达和功能。拟议的研究将揭示非规范但越来越重要的作用 RNA分子转录后处理中的SWI/SNF复合物。 SWI/SNF的新功能 可以在生物技术和药物应用中利用RNA生物学来解决生理 由包括人类在内的真核生物中RNA处理功能障碍引起的疾病。 呢