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Novel Functions for Sm-class RNAs in the regulation of gene expression

Sm 类 RNA 在基因表达调控中的新功能

基本信息

批准号：
9908104
负责人：
Demian Cazalla
金额：
$ 32.03万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908104
关键词：
Animals Apoptosis Binding Binding Proteins Biochemical Biochemistry Biological Testing Cell Death Cell Proliferation Cell Survival Cells Data Elements Eukaryota Future Gene Expression Gene Expression Regulation Genetic Goals High-Throughput Nucleotide Sequencing Homeostasis Human Human Cell Line Infection Length Malignant Neoplasms Mediating Messenger RNA Metabolism MicroRNAs Molecular Mutation Northern Blotting Oncogenic Pathway interactions Primates Proteins RNA RNA Binding RNA Splicing RNase protection assay Regulation Reporter Repression Research Reverse Transcriptase Polymerase Chain Reaction Role Saimiriine Herpesvirus 2 System T-Cell Transformation T-Lymphocyte Testing Trans-Activators Translating Untranslated RNA Viral Viral Cancer cell transformation cofactor combat design experimental study gammaherpesvirus leukemia/lymphoma mRNA Precursor novel novel therapeutics protein complex public health relevance recruit tumorigenesis virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Non-coding RNAs (ncRNAs) have emerged as key players in genetic regulatory systems. Sm-class RNAs constitute a group of ncRNAs with essential roles in important metabolic processes such as pre-mRNA splicing and 3ʹ′-end processing. However, additional Sm-class RNAs have been identified, and we have obtained evidence that they function in gene regulation. We now propose to characterize the targets and mechanisms of action of this distinct new functional subset of Sm-class RNAs. This proposal focuses on determining the functions of novel Sm-class RNAs of both viral and cellular origin. Herpesvirus saimiri (HVS) is an oncogenic γ-herpesvirus that infects T cells and causes aggressive lymphomas and leukemias in New World primates. HVS expresses seven Sm-class RNAs called HSURs (Herpesvirus saimiri U-rich RNAs), of unknown function. Preliminary studies show that HSURs 1 and 2: i) promote the survival of HVS-transformed T cells, ii) associate with actively translated host mRNAs, iii) also associate with host miRNAs (miR-27, miR-16, and miR-142-3p) and AU-rich element (ARE)-binding proteins, and iv) downregulate the target mRNAs. We therefore hypothesize that HSURs 1 and 2 repress target mRNAs by recruiting inhibitory miRNA and ARE-binding protein complexes. We further hypothesize that these activities rewire key host pathways to inhibit apoptosis of latently infected cells. Our preliminary data also identify several new Sm-class RNAs that appear to be expressed in human cell lines. We now propose to test how viral Sm- class RNAs contribute to HVS-mediated T cell transformation, and to characterize the functions of novel human Sm-class RNAs. This proposal combines biochemistry, genetics, and high-throughput sequencing with the aim of defining which cellular pathways are likely regulated by HVS through HSURs 1 and 2 in latently infected cells (Aim 1), determining how HSURs select and repress their target mRNAs (Aim 2), and characterizing the functions of newly identified human Sm-class RNAs (Aim 3). Completion of these aims will deepen our understanding of host-virus interactions, potentially leading to better therapies to combat these infections. More importantly, it will also expand our understanding of an understudied class of ncRNAs and illuminate a novel mechanism of regulation likely used in the broad range of eukaryotes that express Sm-class ncRNAs.

描述（由申请人提供）：非编码RNA（ncRNA）已成为遗传调控系统的关键参与者。Sm-class RNA是一类在前体mRNA剪接和3 ′端加工等重要代谢过程中发挥重要作用的ncRNA。然而，额外的Sm类RNA已被确定，我们已经获得的证据表明，它们在基因调控功能。我们现在提出的特点的目标和机制的行动，这一独特的新的功能子集的Sm类RNA。这项建议的重点是确定新的Sm类RNA的病毒和细胞来源的功能。松鼠猴疱疹病毒（HVS）是一种致癌的γ-疱疹病毒，感染T细胞并在新世界灵长类动物中引起侵袭性淋巴瘤和白血病。HVS表达七种Sm类RNA，称为HSURs（疱疹病毒saimiri U-rich RNA），功能未知。初步研究表明，HSUR 1和2：i）促进HVS转化的T细胞的存活，ii）与主动翻译的宿主mRNA相关，iii）还与宿主miRNA（miR-27、miR-16和miR-142- 3 p）和富含AU的元件（ARE）结合蛋白相关，iv）下调靶mRNA。因此，我们假设HSUR 1和2通过募集抑制性miRNA和ARE结合蛋白复合物来抑制靶mRNA。我们进一步假设，这些活动重新布线的关键宿主途径，以抑制潜伏感染细胞的凋亡。我们的初步数据还确定了几个新的Sm类RNA，似乎在人类细胞系中表达。我们现在提出测试病毒Sm类RNA如何有助于HVS介导的T细胞转化，并表征新的人类Sm类RNA的功能。该提案结合了生物化学，遗传学和高通量测序，目的是确定HVS可能通过潜伏感染细胞中的HSUR 1和2调节哪些细胞途径（Aim 1），确定HSUR如何选择和抑制其靶mRNA（Aim 2），并表征新鉴定的人类Sm类RNA的功能（Aim 3）。这些目标的实现将加深我们对宿主-病毒相互作用的理解，可能导致更好的治疗方法来对抗这些感染。更重要的是，它还将扩大我们对一类未充分研究的ncRNA的理解，并阐明一种可能用于表达Sm类ncRNA的广泛真核生物的新型调控机制。