A Blessing or A Curse?

Welcome to the dark side of the genome ─ transposable elements. These repetitive sequences comprise around half of the human genome (1), and their intricate control contributes to countless aspects of healthy human physiology and development, from immune regulation to brain function (2).

But, the mysterious capabilities of transposable elements are truly unveiled in diseases such as cancer (3).

From the hidden switches within transposable elements that drive tumor growth (4–6) to the sequence-specific landing sites for cancer-causing proteins (7), are they a blessing for cancer? Not according to some striking new discoveries that place transposable elements at the forefront of potential future treatments (6, 8).

This article explores how transposable elements are a double-edged sword for cancers. On the one hand, they contribute to tumorigenesis, but on the other, they create vulnerabilities in cancer cells that could be targeted with novel therapeutics.

What Are Transposable Elements?

Transposable elements are fragments of DNA composed mainly of repetitive sequences, often from ancient viruses trapped in our genome throughout evolution (9). Most copied and pasted themselves around the genome — hence their “jumping genes” nickname. They’ve shaped genome architecture and, ultimately, evolution in most, if not all, species, from the prokaryotic world to modern-day mammals (9).

While the majority of transposable elements are now fixed in host genomes due to mutations over time, this rich tapestry of DNA sequences creates incredible opportunities for fine-tuning gene expression in different cell types, from the very earliest time points shortly after fertilization to adult neurons (10–12).

However, the sheer number and types of these sequences scattered throughout our DNA present cells with a complex problem.

To Silence or To Activate Transposable Elements?

Each cell must walk a tightrope by activating a few useful transposable elements essential for the function of a particular cell while silencing the vast majority of unhelpful ones. For instance, advances in RNA-seq analysis techniques have discovered over 1000 genes with promoters derived from transposable elements (13). As more cell types, tissues, and tumors are sequenced than ever before this number is steadily rising, especially in tissues of different developmental stages or diseases (5, 6, 11).

The balance of transposable element activation and silencing is primarily achieved by epigenetics. It comprises diverse mechanisms, from DNA methylation to histone modifications and transcription factors (2).

But, things begin to get messy in tumor cells.

How Transposable Elements Drive Cancer

When a cell becomes cancerous, the epigenetic regulation of transposable elements fails, enabling their widespread activation (3, 14). Some transposable elements can hop to different regions in the genome and disrupt tumor suppressor genes, while others might drive oncogenes by acting as alternative promoters or hidden enhancers (3, 14).

Activated transposable elements can influence how cancer develops in a variety of ways.

1. Transposable Elements “Jumping” to New Locations

Only one type of transposable element, LINE-1, can still jump to new genomic locations in humans. Researchers found that, when activated, certain types of LINE-1 can insert into and disrupt tumor suppressor genes in colorectal and many other cancers, potentially driving their progression (15, 16).

2. Transposable Elements as “On” Switches

Many transposable elements have intact “on-off” switches for their expression, known as promoters (9). These switches are usually hidden in healthy cells but can be activated in cancerous cells or those with less DNA methylation (3). Suppose one of these switches is turned “on” near an oncogene. In that case, it could drive high expression of a chimeric oncogenic transcript to accelerate tumor growth and reduce patient survival, a phenomenon known as onco-exaptation (3).

This phenomenon is widespread. A study recently identified over 2,000 tumor-specific transposable element-gene chimeric transcripts across 10,000 tumor samples in 33 cancer types (6). Strikingly, 98% of tumors had at least one chimeric transcript, making them a distinctive feature of the cancer transcriptome (6).

3. Transposable Element-Derived Enhancers

Transposable elements can also act as enhancers to fine-tune the expression of genes in countless cellular and developmental processes, including their coordinated control of some aspects of immune-responsive genes (9, 17).

But, as epigenetic mechanisms fail in cancer, hidden enhancers embedded in transposable element sequences can activate tumor suppressor genes or oncogenes to either reduce or accelerate tumor growth, depending on the cancer type (3).

A Double-Edged Sword

Now, this is all great for the tumor, right?

Not necessarily.

The boost in transposable element transcription in cancer cells can have another unforeseen effect on the tumor. Activated transposable elements create virus-like double-stranded RNA or DNA-RNA hybrids in the cytoplasm that trigger an immune response, so-called “viral mimicry” (18, 19). This “viral mimicry” can induce cell death and could be harnessed to fight malignancies.

Similarly, when transposable elements are tacked onto a gene and form cancer-specific chimeric transcripts, either promoters or alternative exon junctions during splicing, the transcripts can be translated into tumor-specific antigens (4, 6). These tumor-specific proteins act as “friend or foe” flags on the tumor surface, marking the cell for destruction by the immune response.

Transposable Elements as Targets of Future Cancer Therapeutics

Strikingly, researchers now suggest that a vaccine cocktail targeting only 20 of these chimeric protein flags could cover more than 75% of tumor samples in over 27 cancer types (6).

Another study showed the potential of this vaccine strategy by immunizing mice with peptides from certain transposable element-gene exon splice junctions (8). They found that immunization could delay melanoma tumor growth, decrease tumor invasion, and prolong survival in mice (8). These advances have the exciting potential to be future off-the-shelf cancer therapeutic strategies, but there’s a long road to the clinic.

Discoveries Powered by Advanced Analytics

Overall, more studies than ever before are unraveling the hidden complexities of the tumor-specific transposable element-derived RNA and protein landscape in cancer. These discoveries provide phenomenal opportunities for using transposable element-derived products as future biomarkers for early cancer detection while providing exciting avenues for novel therapeutics.

However, researchers could not have made these profound discoveries without advanced data analytics. Transposable elements are highly repetitive, posing an enormous headache for traditional next-generation sequencing data analysis strategies, to the extent that this data is regularly discarded, potentially losing crucial biomarkers or contributors to disease pathology.

With over ten years of experience in all aspects of advanced transposable element data analysis, Nexco Analytics has developed TEnex, a suite of optimized peer-reviewed pipelines to comprehensively characterize all facets of transposable element biology using multimodal data sets. We routinely analyze or reanalyze novel or existing data to understand transposable element expression in bulk and single-cell RNA-seq, their decoration with epigenetic markers or transcription factors, and the detection of chimeric transposable element-gene transcripts and their protein-coding potential by in-silico translation.

Please get in touch with us to see how we can help you unleash the most from your data’s dark genome and discover novel biomarkers or therapeutics of the future.

References

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