The Functions of antisense RNA AS-RBM15 in hematopoiesis

反义RNA AS-RBM15在造血中的作用

• 批准号: 9754123
• 负责人: Xinyang Zhao
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754123
• 关键词: 5' Untranslated Regions; Address; Binding Proteins; Biological Assay; Biological Process; Blood; Bone Marrow Cells; Bone Marrow Transplantation; Cell Line; Cells; Code; Defect; Development; Elements; Genes; Goals; Hematopoiesis; Hematopoietic; Homeobox Genes; Human; Human Genome; Knock-out; Knockout Mice; Knowledge; Length; Leukemic Cell; Maps; Mediating; Megakaryocytes; Messenger RNA; Metabolic stress; Methods; Mission; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Open Reading Frames; Pathway interactions; Proteins; RNA; RNA Splicing; RUNX1 gene; Regulation; Reporting; Research; Role; Signal Transduction; Stress; Subfamily lentivirinae; Subgroup; TP53 gene; Thrombopoietin; Transcriptional Regulation; Translations; Untranslated RNA; WT1 gene; attenuation; biological adaptation to stress; differential expression; endoplasmic reticulum stress; hematopoietic stem cell self-renewal; in vivo; knock-down; mouse model; novel; overexpression; response; small hairpin RNA

Project abstract: The number of long noncoding RNA (lncRNA) genes almost equals to the number of protein coding genes. However, the functions of most of lncRNA genes are unknown. Differential expression of lncRNA genes in different hematopoietic lineages implies that lncRNA genes are important regulators for hematopoiesis. One subgroup of lncRNA genes consists of antisense RNA genes that are transcribed in the opposite direction of their sense counterparts. Many genes important for hematopoiesis such as RBM15, PU.1, WT1, p53 and RUNX1 have antisense counterparts. In this proposed study, we plan to investigate the molecular details on how an antisense RNA (AS-RBM15) of RBM15 gene regulates hematopoiesis. We reported that AS-RBM15 promotes RBM15 protein translation via interaction with the 5'UTR of RBM15 mRNA. Furthermore, AS-RBM15 may promote megakaryocyte differentiation via RBM15-dependent and RBM15-independent pathways. We plan to address the hypothesis that AS-RBM15 regulates hematopoiesis via enhancing protein translation. 1) Determine how the cytoplasmic AS-RBM15 regulates RBM15 protein translation in hematopoietic cells. In this specific aim, we plan to understand how the RNA-RNA interaction involving AS-RBM15 and uORF in 5'UTR of RBM15 mRNA regulates RBM15 protein translation, and what kind of hematopoietic signals regulate AS-RBM15-mediated protein translation. 2) Determine the in vivo biological functions of mouse AS-Rbm15 in hematopoiesis. Although the primary RNA sequences between humans and mice are very different, the biological functions of AS-RBM15 genes may still be conserved. We plan to use mouse leukemia cell lines to investigate AS-Rbm15's molecular functions and to use bone marrow transplantation assays to investigate hematopoiesis in vivo. Accomplishing this proposal will provide us with new paradigms on RNA-mediated regulation, establish methods to study other antisense RNA genes and open up new avenues to understand the roles of long noncoding RNA in normal hematopoiesis.

项目摘要： 长非编码RNA(LncRNA)基因的数量几乎等于蛋白质编码的数量 基因。然而，大多数lncRNA基因的功能尚不清楚。的差异表达 不同造血谱系中的lncRNA基因提示，lncRNA基因是重要的调节基因。 用来做造血的。LncRNA基因的一个亚组由反义RNA基因组成，这些基因 转录的方向与他们的正义对应物相反。许多重要的基因对 造血相关基因如RBM15、PU.1、WT1、P53和RUNX1具有反义表达。在这 拟议的研究，我们计划调查反义RNA(AS-RBM15)如何 RBM15基因对造血功能有调节作用。我们报道了AS-RBM15促进RBM15蛋白的表达 通过与RBM15基因5‘端非编码区的相互作用进行翻译。此外，AS-RBM15可能会促进 巨核细胞通过RBM15依赖和非RBM15途径分化。我们计划 解决AS-RBM15通过增强蛋白质翻译来调节造血的假设。1) 确定细胞质AS-RBM15如何调节造血系统中RBM15蛋白的翻译 细胞。在这个特定的目标中，我们计划了解涉及AS-RBM15的RNA-RNA相互作用 而RBM15基因5‘端非编码区的uORF调控RBM15蛋白的翻译，以及 造血信号调节AS-RBM15介导的蛋白质翻译。2)体内测定 小鼠AS-Rbm15在造血中的生物学作用尽管初级RNA序列 人和小鼠之间有很大的不同，AS-RBM15基因的生物学功能可能仍然 保守的。我们计划利用小鼠白血病细胞系来研究AS-Rbm15‘S的分子功能 并用骨髓移植实验研究体内的造血功能。完成 这一建议将为我们提供关于RNA介导的调控的新范式，建立 研究其他反义RNA基因，为理解长非编码的作用开辟新途径 正常造血中的核糖核酸。