Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation

Abstract

BackgroundTranscriptional 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 FindingsUsing 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/SignificanceOur 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.

LINE-1 in cancer: multifaceted functions and potential clinical implications

“…L1 insertions may alter targetgene expression levels, 35,57 which are influenced by cell type 44 and the orientations of L1 insertion. 35,58 It is reported that sense insertions are more likely to be disruptive, 35 possibly due to the fact that L1 sense strand contains more cryptic polyadenylation sites than antisense strand.…”

“…35,58 It is reported that sense insertions are more likely to be disruptive, 35 possibly due to the fact that L1 sense strand contains more cryptic polyadenylation sites than antisense strand. 57 Generally speaking, L1 insertions are more likely to suppress than to activate target-gene expression. 35 L1 insertions can contribute to tumorigenesis by inactivating tumor suppressor genes (Figure 2a) or activating oncogenes (Figure 2b).…”

“…The L1 sequence contains polyadenylation sites as well as donor and acceptor splice sites that may induce novel alternative splicing via retention, exonization, or polyadenylation of the upstream intronic sequences. 57 These L1-induced SVs may occasionally generate novel protein isoforms with new functions, which may serve as a mutation reservoir for tumor evolution.…”

On the Concept Of Retrotransposons: Controlling Genome and Making Stress Memories

“…Considering that approximately 75% of all known human genes bear Alu sequences within their introns and/or untranslated regions (UTRs) [99] , edited intronic Alu elements may have an impact on the transcript metabolism [98] . Moreover, retrotransposons can influence splicing through exon skipping [100][101][102][103][104][105] , alternative donor or acceptor splice sites [106] , shift of splicing patterns from constitutive to alternative [107] , induction of intron retention and exonization [108][109][110][111] . Second, an outstanding feature of retrotransposons is translational control.…”

Proliferation and copy number variation of BEL-like long terminal repeat retrotransposons within the Diabrotica virgifera virgifera genome

“…Specifically, the integration of transposable elements (TEs) can cause mutations that give rise to phenotypic variation among individuals within populations (McClintock, 1950;Wendel and Wessler, 2000), and may generate genetic novelties that contribute to local adaptations (Gonzalez et al, 2010). TEs can also cause insertional knockout of a gene following integration within an open reading frame (Gahan et al, 2001), or decreased splicing efficiency and aberrant polyadenylation when integrated in an intron (Beeman et al, 1996;Kaer et al, 2011). Additionally, integrations within transcriptional regulatory elements (promoters and enhancers) can affect the expression of nearby genes (Chung et al, 2007).…”