ciRS-7 exonic sequence is embedded in a long non-coding RNA locus.
ciRS-7 exonic sequence is embedded in a long non-coding RNA locus.
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DOI：
10.1371/journal.pgen.1007114
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发表时间：
2017-12
期刊：
影响因子：
4.5
通讯作者：
Salzman J
中科院分区：
文献类型：
--
作者：
Barrett SP;Parker KR;Horn C;Mata M;Salzman J
CIRS-7是一种被广泛研究、高表达和保守的CircRNA。基本上，人们对它的生物发生一无所知，包括它的启动子的位置。一种流行的假设是，CIRS-7是一种特殊的CircRNA，因为它是从一个缺乏相同意义的成熟线性RNA转录本的位置转录而来的。为了研究CIRS-7的生物发生，我们开发了一种定义其启动子的算法，并预测人类CIRS-7启动子与长非编码RNA LINC00632的启动子一致。我们通过多个正交实验分析验证了这一预测。我们还使用计算方法和实验验证来确定CIRS-7外显子序列嵌入在人类和小鼠的线性转录本中，这些转录本的两侧都有隐藏的外显子。综上所述，这些实验和计算证据为该基因座的调控产生了一个新的模型：(A)CIRS-7与其他CircRNAs一样，因为它被剪接成线性转录本；(B)CIRS-7的表达主要由LINC00632启动子的染色质状态决定；(C)足够用于CIRS-7生物发生的转录和剪接因子在缺乏检测到CIRS-7表达的细胞中表达。这些发现对研究CIRS-7的调控和功能具有重要意义，我们开发的联合分析RNA-SEQ和CHIP-SEQ数据的分析框架揭示了在全基因组范围内发现当前参考注释中缺失的重要生物调控的可能性。CircRNAs最近被发现是宿主基因表达程序的重要产物，但人们对其转录调控知之甚少。在这里，我们研究了一个名为CIRS-7的具有功能和高表达的CircRNA的表达。CIRS-7对CircRNA有一种不寻常的功能；它被认为是一种miRNA海绵。此前，CIRS-7被认为是从一个缺乏任何成熟线性异构体的基因座转录而来的，不像已知的所有其他在人类细胞中表达的环状RNA。然而，我们发现这是错误的；使用生物信息学和实验遗传学方法的组合，在人类和小鼠中，我们发现了包含CIRS-7外显子序列的线性转录本，将其与上游基因联系起来。这表明这个重要的基因座可能具有更多的功能作用，并为开始研究CIRS-7的生物发生提供了关键信息。
ciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. To study the biogenesis of ciRS-7, we developed an algorithm to define its promoter and predicted that the human ciRS-7 promoter coincides with that of the long non-coding RNA, LINC00632. We validated this prediction using multiple orthogonal experimental assays. We also used computational approaches and experimental validation to establish that ciRS-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. Together, this experimental and computational evidence generates a new model for regulation of this locus: (a) ciRS-7 is like other circRNAs, as it is spliced into linear transcripts; (b) expression of ciRS-7 is primarily determined by the chromatin state of LINC00632 promoters; (c) transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. These findings have significant implications for the study of the regulation and function of ciRS-7, and the analytic framework we developed to jointly analyze RNA-seq and ChIP-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations. circRNAs were recently discovered to be a significant product of ‘host’ gene expression programs but little is known about their transcriptional regulation. Here, we have studied the expression of a functional and highly expressed circRNA named ciRS-7. ciRS-7 has an unusual function for a circRNA; it is believed to be a miRNA sponge. Previously, ciRS-7 was thought to be transcribed from a locus lacking any mature linear isoforms, unlike all other circular RNAs known to be expressed in human cells. However, we have found this to be false; using a combination of bioinformatic and experimental genetic approaches, in both human and mouse, we discovered linear transcripts containing the ciRS-7 exonic sequence, linking it to upstream genes. This suggests the potential for additional functional roles of this important locus and provides critical information to begin study on the biogenesis of ciRS-7.
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影响因子：
48
作者：
Engstrom, Par G.;Steijger, Tamara;Sipos, Botond;Grant, Gregory R.;Kahles, Andre;Raetsch, Gunnar;Goldman, Nick;Hubbard, Tim J.;Harrow, Jennifer;Guigo, Roderic;Bertone, Paul
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Bertone, Paul
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影响因子：
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作者：
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