Half or more of the draft sequence of the human genome consists of interspersed repetitive DNA sequences. These sequences or elements can be transposed and are called transposable elements (TE). It was first discovered 70 years ago by McClintock [2].
Transposable elements (TE) are DNA sequences that can integrate elsewhere in a genome. TEs have been observed in almost all eukaryotic genomes sequenced. TEs are divided into two main classes: Retrotransposons (class 1) and DNA Transposons. Retrotransposons can be transposed thanks to an RNA intermediate, whereas DNA Transposons can be transposed without an RNA intermediate.
There are 3 main Retrotransposons: Long terminal repeat (LTR) retrotransposons, Long interspersed elements (LINEs), and Short interspersed elements (SINEs). Retrotransposons multiply by the copy-paste amplification mechanism that allows them to accumulate in DNA, causing their repetitions to occur in eukaryotic genomes.
The only active autonomous retrotransposon class in humans is LINE-1, which contains two crucial ORFs (open reading frames): ORF-1 encodes an RNA-binding protein. In contrast ORF-2 encodes a protein with reverse transcriptase and endonuclease activities. In the next step, these proteins recognize the specific sequence at the 3' end of the LINE transcript that encodes them and create two-step nicks at the specific sequences. It uses the genomic sequence as a primer and simultaneously converts LINE RNA into cDNA by reverse transcription [1].
“Mobile SINEs are RNA polymerase III (Pol III)-transcribed non-autonomous retrotransposons that do not code for any protein but retro transpose by hijacking the RT and endonuclease activities of a LINE-encoded partner protein.
Primitive LINEs and SINEs have high GC content, making them suitable sites for DNA methylation, which cells use to repress transcription [2].
Recently, Transposable Elements have been investigated on the grounds that they took part in the genome evolution. It was then found to contain functional binding zones for transcription factors. According to a recent data, it has been observed that 44%of the open chromatin regions in the human genome are in TES and that they cover 63%of the regions that control primate specific gene expression [3].
However, the activation of retrotransposons is thought to be harmful. First of all, the products of retrotransposons, including mRNA, proteins and cDNA, can contribute to diseases such as neurodegenerative disorders or cancer. Secondly, their motion may cause DNA damage, mutations, infertility and aging. For this reason, the investigation of mechanisms that silenced retrotransposons in the germ line and somatic cells began.
Transposons and genes combine to form genomes
Non-coding sequences constitute the majority of eukaryotic genomes. Repeated elements, intergenic DNA, and introns are examples of these non-coding sequences. High-copy transposable elements (TEs) are the source of a significant amount of the repeating elements. Given that TEs account for a substantial portion of the genome volume, it is assumed that they have contributed to changes in genome size that have occurred throughout speciation and evolution. There may be significant distinctions between genes and TEs, according to several research on chromatin changes and genome function. Recombination seems to happen often inside genes, but not often at TEs.
The functions of transposable elements in human cells
TEs have the ability to create new genes with essential host roles [4]. Inflammation, the epithelial to mesenchymal transition, and adaptive traits including stress tolerance, accelerated gene replication, raised gene expression, and ageing are all regulated by TEs, according to many studies [5, 6]. In synaptic plasticity, cognition, and tissue development and morphogenesis, transposable elements play a valuable role [7, 8].
The expression of transposon elements induces a cytokine response and leads to the recruitment and infiltration of immune cells in cancer and other inflammatory conditions [9–13]. Apart from their functions in causing genomic instability and altering human genes, human endogenous retroviruses have also been connected to the stimulation and inhibition of the host immune system [14].
Detrimental function of transposable elements
Due to their intrinsic mobility throughout the genome, TEs can cause genomic/epigenetic instability, leading to various disease conditions, cell death, or the onset of cancer. In addition, TEs frequently cause gene disruption and significant genomic abnormalities, such as inversions, deletions, and duplications. TE transposition may occur less often in somatic cells during germline development [12]. The detrimental effects of germline transpositions have been shown throughout time by many examples from a variety of species and transposon classes (Fig. 1).
Transposable elements contribute to the onset of cancer
Numerous studies have shown that somatic TE insertions may upregulate oncogenes and cause genomic rearrangements, which can promote various cancer types [15–17]. The majority of malignancies, including ovarian, colonic, and Fanconi anemia cancer, have shown that transposable elements are capable of escaping epigenetic silencing. Pancreatic ductal adenocarcinoma [18] and esophageal squamous cell carcinoma [19] have both been shown to exhibit insertional mutagenesis, or the integration of L1 retrotransposons into new sites, as a result of dysregulated chromatin modification and lower methylation levels (hypomethylation) in these cancers.
Alternative splicing raises the incidence and development of several cancer types by controlling cellular pathways relevant to cancer [20, 21]. TEs that possess the genetic ability to hop to different regions of the genome regions may be the source of alternative splicing events in cancer [22]. TEs can integrate into the genome, mainly in the intronic regions, and induce cancer-specific alternative splicing by modifying a variety of mechanisms, such as exonization, supplying splicing donor/acceptor sites, alternative regulatory sequences or stop codons, driving exon disruption, or epigenetic regulation [23].
Transbosable Elements and Neurological diseases
In addition to cancer, it is now recognized that TEs are associated with the development of other brain disorders, such as autism and schizophrenia [24–27]. L1 insertions that were selectively localized to genes relevant to synapses and schizophrenia were identified using whole-genome sequencing of the brains of individuals with schizophrenia. This may have contributed to the etiology and vulnerability of schizophrenia by causing L1 retrotransposons to become hyper activated [28]. Furthermore, aberrant activation and mobilization of TEs have been associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease [29]. Guo et al. have shown an interesting correlation between the occurrence of neurofibrillary tangles in post-mortem human brains and the differential expression of many TEs. This suggests a relationship between TE activation and genomic instability in Tau-mediated AD processes. There are some conclusions from studies on the treatment of these diseases (Table 1).
Table 1
Understanding the effects of retrotransposons on gene expression requires further research, as uncovering these mechanisms may aid in the development of novel therapeutic strategies.
| Aspect | Description |
| Regulation of Gene Expression | Retrotransposons can influence nearby gene expression by inserting into regulatory regions like promoters, enhancers, or silencers. They can activate or repress gene expression. |
| Epigenetic Regulation | Retrotransposons can alter gene expression through changes in DNA methylation and histone modifications at insertion sites, affecting chromatin structure and gene accessibility. |
| Transcriptional Interference | The transcriptional activity of retrotransposons can interfere with nearby gene expression by producing noncoding RNA transcripts or influencing chromatin accessibility. |
| Evolutionary Impacts | Retrotransposon insertions contribute to genome evolution by creating genetic diversity and facilitating the emergence of novel genes and regulatory elements. They may also cause genomic instability and diseases if they disrupt essential genes or regulatory networks. |