State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
J Genet Genomics. 2015 Aug 20;42(8):423-36. doi: 10.1016/j.jgg.2015.07.001. Epub 2015 Jul 10.
Although there is an accumulating appreciation of the key roles that long intergenic non-coding RNAs (lincRNAs) play in diverse cellular processes, our knowledge of how lincRNAs function in cancer remains sparse. Here, we present a comprehensive landscape of RNA-seq transcriptome profiles of lung adenocarcinomas and their paired normal counterparts to unravel gene regulation rules of lincRNAs. Consistent with previous findings of co-expression between neighboring protein-coding genes, lincRNAs were typically co-expressed with their neighboring genes, which was found in both cancerous and normal tissues. By building a mathematical model based on correlated gene expression, we distinguished an additional subset of lincRNAs termed "regulatory lincRNAs", representing their dominant roles in gene regulation. The number of regulatory lincRNAs was significantly higher in cancerous compared to normal tissues, and most of them positively regulated protein-coding genes in trans. Functional validation, using knockdown, determined that regulatory lincRNA, GAS5, affected its predicted protein-coding targets. Moreover, we discovered hundreds of differentially expressed regulatory lincRNAs with inclusion of some cancer-associated lincRNAs. Our integrated analysis reveals enhanced regulatory effects of lincRNAs and provides a resource for the study of regulatory lincRNAs that play critical roles in lung adenocarcinoma.
尽管人们越来越认识到长非编码 RNA（lncRNA）在多种细胞过程中发挥的关键作用，但我们对 lncRNA 在癌症中的功能知之甚少。在这里，我们展示了肺腺癌及其配对正常组织的 RNA-seq 转录组谱的全面图谱，以揭示 lncRNA 的基因调控规则。与邻近蛋白编码基因之间的共表达的先前发现一致，lncRNA 通常与邻近基因共表达，这在癌组织和正常组织中均有发现。通过基于相关基因表达构建数学模型，我们区分了另一组称为“调控 lncRNA”的 lncRNA，代表它们在基因调控中的主要作用。与正常组织相比，癌组织中的调控 lncRNA 数量明显更多，并且大多数以反式方式正向调控蛋白编码基因。使用敲低进行功能验证确定，调控 lncRNA，GAS5，影响其预测的蛋白编码靶标。此外，我们发现了数百个差异表达的调控 lncRNA，其中包括一些与癌症相关的 lncRNA。我们的综合分析揭示了 lncRNA 增强的调控作用，并为研究在肺腺癌中发挥关键作用的调控 lncRNA 提供了资源。
