Figure 2. How L1 insertion may affect the transcriptome.

A| In a process termed transduction, L1 elements (golden cylinders) carry sequences flanking the element from their original source location to a new location; this can occur on the 5′ and 3′ end: transcription that initiates upstream from the L1 element results in mRNA that contains additional sequence 5′ of the L1 element (red line), whereas poly-adenylation sites that are located further downstream of the L1 element can lead to extension of L1 mRNA beyond the element’s 3′ end (green line). This process can cause exon shuffling or lead to insertion of regulatory sequences such as transcription factor binding sites at a new genomic location.

B| Mammalian L1 elements (golden cylinders) contain functional splice sites in both sense and antisense (AS) orientations; thus, when integrated into introns, L1 elements can induce aberrant splicing resulting in alternative mRNA transcripts.

C| L1 elements contain numerous internal polyadenylation [(p(A)] signals in both sense and antisense orientation that can lead to alternative mRNA transcripts or premature termination, thus affecting mRNA splicing and stability.

D| Transcript levels of genes can be changed through regulatory sequences that are contained within L1 elements. Human L1 elements contain one sense and one antisense promoter within their 5′ UTR and another promoter in the 3′ UTR (bent arrows). The antisense promoter in the 5′ and 3′ UTRs can initiate ectopic transcription of sequences flanking L1. Antisense transcripts can lead to production of non-coding RNA (ncRNA) or chimeric transcripts. Further, antisense RNA could reduce mRNA levels through the formation of double-stranded RNA (dsRNA), triggering the protein kinase R (PKR) degradation pathway [81], or leading to siRNA that induces RISC-dependent silencing [82]. In addition, ncRNAs could modulate epigenetic marks in cis and aid in the establishment of boundary elements.

E| An L1 element that has inserted upstream of another gene can become methylated (Me), which may induce formation of heterochromatin (red ovals) that can spread into flanking promoter sequences, effectively silencing transcription. Conversely, activation of an inserted L1 element could lead to ectopic activation of a nearby gene by facilitating binding of transcription factors (green oval).