Molecular mechanistic studies of long “noncoding” RNAs in mammalian cell differentiation

哺乳动物细胞分化中长“非编码”RNA 的分子机制研究

基本信息

批准号：
10538558
负责人：
Wenqian Hu
金额：
$ 31.8万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538558
关键词：
Address Amino Acids Antisense RNA Area Automated Annotation Biological Process Biology Categories Cell Differentiation process Cell Maturation Cell Nucleus Cell Size Cells Chromatin Classification Code Collaborations Computational algorithm Confusion DLEU2 gene Discrimination Disease Erythrocytes Erythroid Cells Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Goals Homologous Gene Human In Vitro Inflammatory Inflammatory Response Inhibition of Apoptosis Knockout Mice Knowledge Macrophage Malignant Neoplasms Mammalian Cell Mediating Messenger RNA Methods Modeling Molecular Molecular Biology Mus Nuclear Open Reading Frames Pathologic Physical condensation Physiological Play Process Proteins RNA Regulator Genes Ribosomes Role Specificity System Tertiary Protein Structure Transcript Untranslated RNA Work cell type diagnostic biomarker differential expression erythroid differentiation experimental study human disease insight leukemia loss of function mouse model novel polypeptide ribosome profiling stem cells therapeutic target tool transcriptomics

项目摘要

PROJECT SUMMARY The goal of this study is to determine the molecular mechanisms by which long “noncoding” RNAs regulate mammalian cells differentiation. Long noncoding RNAs (lncRNAs), defined as RNAs longer than 200nt without functional protein coding capacity, are emerging regulators of gene expression. Genomic studies revealed that many lncRNAs are differentially expressed in a wide variety of biological processes. Although an increasing number of lncRNAs are observed to play important roles under many physiological and pathological conditions, the molecular mechanisms they use to control gene expression are still unknown for a lot of lncRNAs. Thus, mechanistically characterizing functionally important lncRNAs in mammalian cells is of high significance to both RNA molecular biology and potential usage of these RNAs as diagnostic markers and therapeutic targets. Using the terminal differentiation of erythroid cells as a model, our recent studies revealed that lncRNAs can be classified into bona fide lncRNAs and small-polypeptide-encoding “lncRNAs” based on their functional association with the cellular translational apparatus, the ribosome. Notably, we observed that lncRNAs from each of these two categories play critical roles in this important cell differentiation process. Thus, we plan to mechanistically dissect how bona fide lncRNAs and small-polypeptide-encoding “lncRNAs” regulate gene expression in mammalian cell differentiation, respectively. The results from this study will not only fill a fundamental knowledge gap in lncRNA biology, the molecular mechanisms of lncRNAs, but also may potentially provide insights for human diseases, as one of the lncRNAs we will study, Dleu2, is frequently deleted in certain human leukemias.

项目概要本研究的目的是确定长“非编码”RNA 调节的分子机制哺乳动物细胞分化。长非编码RNA（lncRNA），定义为长度超过200nt的RNA。功能性蛋白质编码能力，是基因表达的新兴调节因子。许多 lncRNA 在多种生物过程中都有差异表达，尽管这一趋势在不断增加。观察到许多lncRNA在许多生理和病理条件下发挥重要作用，对于许多 lncRNA 来说，它们用于控制基因表达的分子机制仍然未知。从机制上表征哺乳动物细胞中功能重要的lncRNA对于两者都具有重要意义 RNA 分子生物学以及这些 RNA 作为诊断标记和治疗靶点的潜在用途。我们最近的研究以红系细胞的终末分化为模型，表明lncRNA可以根据其功能分为真正的lncRNA和小多肽编码的“lncRNA” 值得注意的是，我们观察到lncRNAs与细胞翻译装置核糖体的关联。这两个类别中的每一个都在这个重要的细胞分化过程中发挥着关键作用。从机制上剖析真正的lncRNA和小多肽编码“lncRNA”如何调节基因这项研究的结果不仅将填补哺乳动物细胞分化中的表达。 lncRNA生物学的基础知识差距，lncRNA的分子机制，但也可能潜在地为人类疾病提供见解，因为我们将研究的 lncRNA 之一 Dleu2 经常被在某些人类白血病中被删除。