Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.
Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.
复制标题
DOI：
10.1371/journal.pgen.1005001
复制
发表时间：
2015-02
期刊：
影响因子：
4.5
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Qin F;Song Z;Babiceanu M;Song Y;Facemire L;Singh R;Adli M;Li H
除非在某些疾病情况下，基因或其编码产物不会相互混合。在癌症中，染色体重排是导致基因融合的常见机制。然而，最近发现的RNA反式剪接和相邻基因之间的顺式剪接（cis-SAGe）支持了产生融合RNA的其他机制。在我们对28个前列腺正常和癌症样本的转录组分析中，平均30%的融合rna是包含属于同链邻近基因的外显子的转录本。这些融合rna可能是cis-SAGe的产物，这在以前被认为是罕见的。为了验证这一发现并更好地理解这一现象，我们使用LNCaP（一种前列腺细胞系）作为模型，并通过沉默转录因子CTCF和配对端RNA测序确定了16个额外的顺式sage事件。与亲本基因相比，大约一半的融合基因的表达水平显著。沉默其中一个框架内融合导致细胞运动性降低。大多数框架外融合可能作为非编码rna发挥作用。在其他前列腺细胞系以及14对临床前列腺正常和癌对中也检测到16种融合。通过研究这些融合的相关特征，我们得出了一套规则：1)亲本基因是同链邻近基因；2)基因间距离在30kb以内；3) 5′基因转录活跃；4)嵌合体倾向于将5 ‘基因的倒数第二个外显子连接到3 ’基因的第二个外显子上。然后，我们在基因组中随机选择了20个邻近基因，并使用这些规则在前列腺癌和非癌细胞中检测了四个融合事件。这些结果表明，邻近基因转录物之间的剪接是一种相当频繁的现象，而不是癌细胞特有的特征。基因被认为是遗传信息的单位；因此，除非在某些疾病情况下，否则基因及其编码产物都不会相互混合。然而，这些基因在基因组中并不孤单。基因有邻居，有的近，有的远。利用RNA-seq，许多涉及邻近基因的融合rna被鉴定出来。然而，很少有人对融合rna进行验证和表征。利用一个前列腺细胞系和一个相邻基因间顺式剪接的发现管道（cis-SAGe），我们发现了16个新的这样的事件。然后，我们根据这些融合rna的特征制定了一套规则，并将其应用于20个随机相邻的基因对。事实证明，其中四个是正确的。大多数融合存在于癌细胞和非癌细胞中。这些结果表明，基因是“漏的”，融合并不局限于癌细胞。
Genes or their encoded products are not expected to mingle with each other unless in some disease situations. In cancer, a frequent mechanism that can produce gene fusions is chromosomal rearrangement. However, recent discoveries of RNA trans-splicing and cis-splicing between adjacent genes (cis-SAGe) support for other mechanisms in generating fusion RNAs. In our transcriptome analyses of 28 prostate normal and cancer samples, 30% fusion RNAs on average are the transcripts that contain exons belonging to same-strand neighboring genes. These fusion RNAs may be the products of cis-SAGe, which was previously thought to be rare. To validate this finding and to better understand the phenomenon, we used LNCaP, a prostate cell line as a model, and identified 16 additional cis-SAGe events by silencing transcription factor CTCF and paired-end RNA sequencing. About half of the fusions are expressed at a significant level compared to their parental genes. Silencing one of the in-frame fusions resulted in reduced cell motility. Most out-of-frame fusions are likely to function as non-coding RNAs. The majority of the 16 fusions are also detected in other prostate cell lines, as well as in the 14 clinical prostate normal and cancer pairs. By studying the features associated with these fusions, we developed a set of rules: 1) the parental genes are same-strand-neighboring genes; 2) the distance between the genes is within 30kb; 3) the 5′ genes are actively transcribing; and 4) the chimeras tend to have the second-to-last exon in the 5′ genes joined to the second exon in the 3′ genes. We then randomly selected 20 neighboring genes in the genome, and detected four fusion events using these rules in prostate cancer and non-cancerous cells. These results suggest that splicing between neighboring gene transcripts is a rather frequent phenomenon, and it is not a feature unique to cancer cells. Genes are considered the units of hereditary information; thus, neither genes nor their encoded products are expected to mingle with each other unless in some disease situations. However, the genes are not alone in the genome. Genes have neighbors, some close, some far. With RNA-seq, many fusion RNAs involving neighboring genes are being identified. However, little is done to validate and characterize the fusion RNAs. Using one prostate cell line and a discovery pipeline for cis-splicing between adjacent genes (cis-SAGe), we found 16 new such events. We then developed a set of rules based on the characteristics of these fusion RNAs, and applied them to 20 random neighboring gene pairs. Four turned out to be true. The majority of the fusions are found in cancer cells, as well as in non-cancer cells. These results suggest that the genes are “leaky”, and the fusions are not limited to cancer cells.
登录
查看更多内容
影响因子：
--
作者：
Ong CT;Corces VG
通讯作者：
Corces VG
DOI：
10.1038/nrg3663
发表时间：
2014-04
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Ong CT;Corces VG
通讯作者：
Corces VG
影响因子：
7
作者：
Akiva, P;Toporik, A;Sorek, R
通讯作者：
Sorek, R
DOI：
10.1073/pnas.162342499
发表时间：
2002-12-10
影响因子：
11.1
作者：
Burgess-Beusse, B;Farrell, C;Felsenfeld, G
通讯作者：
Felsenfeld, G
影响因子：
3.3
作者：
Machida, Yuichi J.;Chen, Yuefeng;Dutta, Anindya
通讯作者：
Dutta, Anindya