Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation
Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation
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DOI：
10.1371/journal.pone.0026099
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发表时间：
2011-10-13
期刊：
影响因子：
3.7
通讯作者：
Speek, Mart
中科院分区：
文献类型：
--
作者：
Kaer, Kristel;Branovets, Jelena;Speek, Mart
背景：转录干扰是近年来发现的一种异常复杂的基因负调控机制。尽管近年来出现了相对较少的研究，但已经证明来自一个基因的通读转录可以影响另一个重叠或嵌套基因的转录。然而，这种相互作用产生的分子效应在很大程度上是unknown. Methodology/Principal Findings：使用计算机染色体步移，我们寻找提前终止的转录本轴承签名的内含子保留或外显子的内含子序列在其3 '端上游的人L1反转录转座子，蛋白质编码和非编码嵌套基因。我们证明，内含子L1（或其他重复DNA）和嵌套基因诱导的转录干扰的特点是内含子保留，强制外显子和隐蔽的多聚腺苷酸化。这些分子效应从来自不同细胞系和组织的内源性转录物的分析中揭示，并通过细胞培养物中三个小基因的表达来证实。而内含子保留和外显子的内含子上游观察到L1，强制外显子优先检测嵌套基因。转录干扰诱导的L1或嵌套基因是依赖于隐蔽剪接位点的存在或不存在，影响上游外显子的列入或排除和使用隐蔽polyadenylation signals.Conclusions/Significance：我们的研究结果表明，转录干扰诱导的内含子L1s和嵌套基因可以影响大量的基因在正常以及在肿瘤组织中的转录。因此，这种类型的干扰可能对宿主基因表达的调控产生重大影响。
Background: Transcriptional interference has been recently recognized as an unexpectedly complex and mostly negative regulation of genes. Despite a relatively few studies that emerged in recent years, it has been demonstrated that a readthrough transcription derived from one gene can influence the transcription of another overlapping or nested gene. However, the molecular effects resulting from this interaction are largely unknown.Methodology/Principal Findings: Using in silico chromosome walking, we searched for prematurely terminated transcripts bearing signatures of intron retention or exonization of intronic sequence at their 3' ends upstream to human L1 retrotransposons, protein-coding and noncoding nested genes. We demonstrate that transcriptional interference induced by intronic L1s (or other repeated DNAs) and nested genes could be characterized by intron retention, forced exonization and cryptic polyadenylation. These molecular effects were revealed from the analysis of endogenous transcripts derived from different cell lines and tissues and confirmed by the expression of three minigenes in cell culture. While intron retention and exonization were comparably observed in introns upstream to L1s, forced exonization was preferentially detected in nested genes. Transcriptional interference induced by L1 or nested genes was dependent on the presence or absence of cryptic splice sites, affected the inclusion or exclusion of the upstream exon and the use of cryptic polyadenylation signals.Conclusions/Significance: Our results suggest that transcriptional interference induced by intronic L1s and nested genes could influence the transcription of the large number of genes in normal as well as in tumor tissues. Therefore, this type of interference could have a major impact on the regulation of the host gene expression.