Roles of long noncoding RNAs in neural differentiation

细胞分化依赖于基因表达的广泛变化，几乎影响到所有类别的转录本。哺乳动物基因组编码数千个长的非编码RNA(LncRNAs)，这些RNA缺乏功能开放阅读框架。尽管在过去的几年里，这些RNA物种已经引起了相当大的研究兴趣，但它们在细胞增殖、分化和生存中的作用仍然知之甚少。我们最近发现了一类新的富含短串联重复序列(STR)的LncRNAs，即2-12个核苷酸长的“单词”的多次重复[1]。这些转录本的一个有趣的特性是它们可以与特定RNA结合蛋白(RBPs)的多个副本相互作用，RBPs是细胞RNA代谢的一组不同的调节因子。到目前为止，我们已经分析了一个STR-lncRNAs的例子，我们称之为PNCTR。PNCTR包含与嘧啶结合蛋白(PTBP1)相互作用的短链受体，它允许这种RNA通过将PTBP1隔离在称为核周室的核体中来促进细胞存活[1]。我们正在进行的生物信息学分析表明，人类和小鼠的基因组编码了数百个含有STR的lncRNAs，其中包括许多异染色质区域表达的转录本。这反过来又表明了一种令人兴奋的可能性，即lncRNAs控制着一个大型限制性商业惯例网络的活动，该网络可能在染色质和核组织中发挥作用。鉴于基于RNA的调节机制在神经系统中的重要性，以及我们长期以来对负责获得和维持神经细胞特性的分子机制的兴趣[2-4]，我们建议调查STR-lncRNAs在发育中的大脑中的作用。该项目将追求以下相互关联的目标：1.了解含有异染色质相关重复序列的lncRNAs在人类诱导的多能干细胞和神经谱系中的生物学功能。2.利用生物信息学方法系统地发现在发育神经谱系过程中存在差异调控的含有STR的lncRNAs。3.深入分析生物信息学调查确定的最感兴趣的候选人(S)的功能意义。

Cell differentiation relies on extensive changes in gene expression affecting virtually all categories of transcripts. Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs) that lack functional open reading frames. Although these RNA species have attracted considerable research interest over the last few years, their roles in cell proliferation, differentiation and survival remain poorly understood. We have recently identified a new class of lncRNAs enriched in short tandem repeats (STRs),multiple iterations of 2-12 nucleotide-long "words" [1]. An interesting property of these transcripts is that they can interact with multiple copies of specific RNA-binding proteins (RBPs), a diverse group of regulators of cellular RNA metabolism. So far, we have analysed a single example of STR-lncRNAs, a transcript that we termed PNCTR. PNCTR contains STRs interacting with pyrimidine tract-binding protein (PTBP1), which allow this RNA to promote cell survival by sequestering PTBP1 in a nuclear body called perinucleolar compartment [1]. Our ongoing bioinformatics analyses suggest that the human and mouse genomes encode hundreds of STR-containing lncRNAs including many transcripts expressed from heterochromatic regions. This in turn points at an exciting possibility that lncRNAs control activity of a large network of RBPs with possible roles in chromatin and nuclear organization. Given the importance of RNA-based regulation mechanisms in the nervous system and our long-standing interest in molecular mechanisms responsible for acquisition and maintenance of neural cell identities [2-4], we propose to investigate the role of STR-lncRNAs in the developing brain.The project will pursue the following interrelated objectives: 1. Understanding biological functions of heterochromatin-associated repeat-containing lncRNAs in human induced pluripotent stem cells and the neural lineage. 2. Systematic discovery of STR-containing lncRNAs differentially regulated in developing neural lineage using bioinformatics approaches. 3. In-depth analysis of functional significance of the most interesting candidate(s) identified by the bioinformatics survey.