Winkle Melanie, van den Berg Anke, Tayari Masoumeh, Sietzema Jantine, Terpstra Martijn, Kortman Gertrud, de Jong Debora, Visser Lydia, Diepstra Arjan, Kok Klaas, Kluiver Joost
*Department of Pathology and Medical Biology and Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
*Department of Pathology and Medical Biology and Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
FASEB J. 2015 Jun;29(6):2338-46. doi: 10.1096/fj.14-263889. Epub 2015 Feb 17.
Myc is a well-known transcription factor with important roles in cell cycle, apoptosis, and cellular transformation. Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory RNAs. Here, we show that lncRNAs are a main component of the Myc-regulated transcriptional program using the P493-6 tetracycline-repressible myc model. We demonstrate that both Myc-induced mRNAs and lncRNAs are significantly enriched for Myc binding sites. In contrast to Myc-repressed mRNAs, Myc-repressed lncRNAs are significantly enriched for Myc binding sites. Subcellular localization analysis revealed that compared to mRNAs, lncRNAs more often have a specific subcellular localization with a markedly higher percentage of nuclear enrichment within the Myc-repressed lncRNA set. Parallel analysis of differentially expressed lncRNAs and mRNAs identified 105 juxtaposed lncRNA-mRNA pairs, indicative for regulation in cis. To support the potential relevance of the Myc-regulated lncRNAs in cellular transformation, we analyzed their expression in primary Myc-high and Myc-low B-cell lymphomas. In total, 54% of the lncRNAs differentially expressed between the lymphoma subsets were identified as Myc-regulated in P493-6 cells. This study is the first to show that lncRNAs are an important factor within the Myc-regulated transcriptional program and indicates a marked difference between Myc-repressed lncRNAs and mRNAs.
Myc是一种著名的转录因子，在细胞周期、细胞凋亡和细胞转化中发挥着重要作用。长链非编码RNA（lncRNA）最近已成为一类重要的调控RNA。在此，我们使用P493 - 6四环素可抑制的myc模型表明，lncRNA是Myc调控转录程序的主要组成部分。我们证明，Myc诱导的mRNA和lncRNA都显著富集了Myc结合位点。与Myc抑制的mRNA不同，Myc抑制的lncRNA显著富集了Myc结合位点。亚细胞定位分析显示，与mRNA相比，lncRNA更常具有特定的亚细胞定位，在Myc抑制的lncRNA组中核富集百分比明显更高。对差异表达的lncRNA和mRNA进行平行分析，鉴定出105对并列的lncRNA - mRNA对，表明存在顺式调控。为了支持Myc调控的lncRNA在细胞转化中的潜在相关性，我们分析了它们在原发性Myc高和Myc低的B细胞淋巴瘤中的表达。总共，淋巴瘤亚组之间差异表达的lncRNA中有54%被鉴定为在P493 - 6细胞中受Myc调控。这项研究首次表明lncRNA是Myc调控转录程序中的一个重要因素，并表明Myc抑制的lncRNA和mRNA之间存在显著差异。
