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

项目摘要 这项研究的目的是确定长的“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200 nt的RNA， 功能性蛋白质编码能力，是基因表达的新兴调节因子。基因组研究显示， 许多lncRNA在多种生物过程中差异表达。尽管越来越 许多lncRNA被观察到在许多生理和病理条件下发挥重要作用， 对于许多lncRNA来说，它们用来控制基因表达的分子机制仍然是未知的。因此，在本发明中， 在哺乳动物细胞中机械地表征功能重要的lncRNA对于以下两个方面都具有高度意义： RNA分子生物学和这些RNA作为诊断标记物和治疗靶点的潜在用途。 以红系细胞的终末分化为模型，我们最近的研究表明，lncRNA可以被 根据其功能分为真正的lncRNA和编码小多肽的“lncRNA”， 与细胞翻译装置核糖体的联系。值得注意的是，我们观察到， 这两类中的每一种在这一重要的细胞分化过程中起关键作用。因此，我们计划 机械地剖析真正的lncRNA和编码小多肽的“lncRNA”如何调节基因， 在哺乳动物细胞分化中的表达。这项研究的结果不仅将填补一个 lncRNA生物学的基本知识缺口，lncRNA的分子机制，但也可能 可能为人类疾病提供见解，因为我们将研究的lncRNA之一Dleu2经常 在某些人类白血病中缺失

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.