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Researchers Identify Jumping “Junk” DNA as a Novel Cause of Paediatric Brain Cancer

Written by Bethany Hoernfeldt, Science Writer 

Researchers at St. Jude Children’s Hospital have discovered the first causal link between “jumping” DNA and paediatric brain cancer. This novel mechanism in tumourigenesis will further unravel the mysteries of the “dark” genome and the effect of its genomic drivers on human health.

In a recent study, researchers at St. Jude Children’s Research Hospital revealed an unexpected driver of childhood brain cancer: the active promoter of a transposon, or “jumping” DNA segment, led to the overexpression of an oncogene – FOXR2. Knowledge surrounding promoter “donation” – a novel disease mechanism – may prove invaluable in the diagnosis and treatment of aggressive and treatment-resistant diseases such as paediatric brain cancer.

Contradicting cancer classification results

A paediatric patient presented with a high-grade glioma – a type of cancer that is infamous for its aggressive nature and resistance to treatment. When classifying the cancer, pathologists found a mismatch between the DNA methylation profile and histology of the tumour. Although the tumour appeared to be a high-grade glioma, the methylation profile reflected that of a FOXR2-driven central nervous system embryonal tumour. This sort of mismatch is rare and demanded further investigation. RNA-Seq data later revealed that the promoter region of a retrotransposon known as a Long Interspersed Element-1 (LINE-1 or L1) bound to the acceptor site of exon 2 of FOXR2, leading to overexpression of the gene.

“Jumping” genes

Transposons are DNA segments of 400 to 600 base pairs long that “bounce” around in the genome. Most transposable elements are inactive and remain bound to their position, while others may integrate into our genes and disrupt normal gene function or regulation. Retrotransposons such as L1s insert themselves into the genome by means of a “copy and paste” mechanism. This means that the original copy is retained while a second copy is inserted elsewhere.

Our genomes harbour 80-100 active L1s on average. They bear a striking resemblance to our genes, in that they contain regulatory elements such as promoters that drive retrotransposition. In this case, the promoter – the “on/off switch” that drives expression of the gene in question – is imbedded into the oncogene FOXR2. As a result, the gene is overexpressed, eventually leading to cancer. The potential impact of retrotransposition on gene function is a familiar concept, but usually the promoter region is lost when L1 is “copied” into another area of the genome. Interestingly, this is the first recorded incidence of cancer driven by L1 promoter “donation” – a finding that serves as a revolutionary step in unravelling the effect of the “dark” genome on disease pathogenesis.

“The L1 promoter ‘donation’ mechanism is entirely novel,” said Junghui Zhang, the corresponding author on the study. “Our study opens the door for people to investigate this mechanism in initiating cancer and other diseases.”

Finding gold in “garbage” data

As the impact of L1 promoter “donation” on carcinogenesis is novel, the corresponding data was deemed irrelevant by the computational algorithm and was subsequently cut out. Luckily, Zhang and his team sifted through the omitted data and spotted what appeared to be an L1 regulatory event and ultimately connected the dots, paving the way for an array of exciting research.

Jason Chang, the co-corresponding author, said, “Scientists need to keep their eyes open for all possibilities. Don’t filter out information that you think is garbage. Sometimes the gold is in the garbage.”

Image Credit: Canva


More on these topics

Cancer / Cancer Research / Dark Genome / Transposons