Genomic Instability Generated by TEs
The TEs inserted in intra- and inter-genic regions could alter cellular gene expression, increasing genomic instability [9]. About a decade ago, gene regulation by TEs was studied only in specific genes through experimental validation. However, genome-wide analyses of gene regulation by TEs were recently conducted due to the developed high-throughput technologies. The findings showed that TEs have many regulatory sequences, such as promoters, enhancers, polyadenylation signals, and cryptic splicing donor (5') and acceptor (3') sites, by which the transcript architecture of nearby genes can be altered [10, 46, 47].
When TEs insert into the intronic region of genes, they could create a new exon by offering splicing sites, and this process is called "exonization" [48]. This mechanism is related to exon variations, such as cassette exons and intron retention in exons, increasing mRNA instability [49]. The TEs residing upstream of any gene could act as an alternative promoter, leading to new alternative transcripts with a new transcriptional start site [10]. Some TEs carry bidirectional promoters with transcription factor binding sites. For example, LTR and L1 have sense promoters initiating their transcription and antisense promoters having the potential to initiate the transcription of other genes in the opposite direction [50, 51]. There is a microRNA gene cluster in human chromosome 19 (C19MC), over 100 kb in length. This cluster consists of the duplication of a core cassette, including a minus-strand Alu element. The cluster grew successfully during primate evolution, and the Alu element promotes microRNA expression by RNA polymerase III [52]. TEs not only initiate transcription but also terminate it by offering a polyadenylation signal. A full-length L1 contains 19 polyadenylation signals that could cause premature mRNA truncation [53]. The genes that contain TEs in their genic region have a tendency to produce various transcript forms, causing transcriptome diversity [10].
The orientation of TEs could be a factor affecting gene expression, which is well described by a "head-on collision" hypothesis. During DNA replication, DNA polymerase collides with RNA polymerase transcription complexes moving in the opposite direction to the movement of the DNA polymerase. It was observed that the collision slows down the DNA replication [54]. In cases where active TE exists in the opposite direction to its nearby genes, an RNA polymerase transcription complex transcribing the TE could encounter any of the RNA polymerase transcription complexes transcribing nearby genes, which could reduce the expression of the gene [54, 55]. In reality, transcription of the E-globin gene is repressed by an Alu element that has been inserted in the opposite direction to the gene [56]. On the other hand, TEs inserting in the same direction to its nearby genes show no effect on the expression of the genes [55].
Histone modification plays an important role in gene transcriptional regulation, and through this process, the host genome could regulate the activation of TEs [57, 58]. In reality, most TEs are accompanied by repressive histone modifications (e.g., H3K9me2 and H3K27me3), which cause the formation of heterochromatin. Conversely, TEs could affect the expression of host genes through histone modifications [59, 60]. The level of histone modifications was calculated in all families of human TEs, and older TE families carried more histone modifications than younger families. Interestingly, TEs proximal to genes carry more histone modifications than the ones that are distal to genes, which suggests that some epigenetic modifications of TEs may serve to regulate the expression of host genes [61].
DNA methylation is a strict silencing mechanism, and the host genome could use this process to repress the activation of TEs [61]. In general, DNA methylation occurs in a CpG dinucleotide. Because Alu and SVA elements have a high degree of CpG dinucleotides, they are vulnerable to methylation [26, 62]. It was observed that TEs regain their activity to mobilize and regulate the expression of host genes when the silencing effect becomes slackened with increasing genomic instability. In addition, the demethylation of TEs is associated with human diseases, commonly in cancer [63-65].
miRNAs, one of the most active factors regulating gene expression, could be derived from TEs. Fifty-five genes derived from TEs were identified in the human genome, and their characterization showed that TE-derived miRNAs could potentially regulate the complex and dynamics of human genes [66].