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

项目总结 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(LncRNAs)，定义为长度超过200nT的RNAs 功能性蛋白编码能力，是基因表达的新兴调节因子。基因组研究表明 许多lncRNAs在多种生物学过程中都有差异表达。尽管不断增加的 许多lncRNA被观察到在许多生理和病理条件下发挥重要作用， 它们用来控制基因表达的分子机制对于许多lncRNA来说仍然是未知的。因此， 哺乳动物细胞中具有重要功能的lncRNAs的机械特征对两者都具有高度的意义 核糖核酸分子生物学及其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，lncRNAs可以 根据它们的功能分为真正的lncRNAs和编码小多肽的lncRNAs 与细胞翻译机构--核糖体有关。值得注意的是，我们观察到来自 这两个类别中的每一个都在这一重要的细胞分化过程中发挥着关键作用。因此，我们计划 真正的lncRNAs和编码小多肽的lncRNAs如何调控基因的机制剖析 分别在哺乳动物细胞分化过程中表达。这项研究的结果不仅将填补 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洞察力，因为我们将研究的lncRNAs之一，Dleu2，经常 在某些人类白血病中被删除。

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.