Scientists at St. Jude Children's Research Hospital have identified new roles for the retrotransposon LINE-1 in shaping the structure and regulation of cancer genomes. Retrotransposons, often called "jumping genes," are mobile DNA elements that make up a large part of the human genome and can move to different locations within it. This mobility has been linked to diseases such as cancer.
The research team discovered a previously unrecognized class of highly interactive LINE-1 loci—regions in the genome—that affect how cancer genes are expressed by changing the three-dimensional (3D) organization of genetic material inside cells. These findings were published in Cancer Discovery, a journal from the American Association for Cancer Research.
LINE-1 is noted as the most common retrotransposon, with an ability to move itself around within the genome. While this activity is usually suppressed in normal cells, it tends to increase significantly in cancer cells. Although LINE-1’s movement can cause genetic changes thought to drive cancer development, evidence suggests that direct oncogenic mutations caused by these events are relatively rare.
"The conundrum is that if this is true, we should see many more oncogenic mutations due to these events," said Jian Xu, PhD, corresponding author and member of the St. Jude Department of Pathology. "However, in both the literature and our analyses, these events are relatively rare. This suggests it can happen, but it may not be a prevalent mechanism for how these retrotransposons drive cancer development."
To explore how abnormal LINE-1 activity contributes to cancer biology beyond causing mutations, Xu's team used a sequencing-based chromatin structure assay capable of reading long stretches of repetitive DNA where retrotransposons reside. This allowed them to study 3D interactions involving LINE-1 elements more closely.
Their research found that RNA produced by younger LINE-1 regions remains attached to chromatin—the complex of DNA and proteins forming chromosomes—and helps bring together distant parts of genetic material within cell nuclei. This reorganization allows for higher expression levels of certain genes involved in driving cancer cell growth.
"Chromatin-associated LINE-1 RNA can recruit specific RNA-binding proteins to assemble high-order chromatin structures at select genomic sites, forming what we call 'HILLs' - highly interactive LINE-1 loci," explained Xu. "In other words, these HILLs act to stitch different parts of the chromatin together to create an environment where oncogenes can be better expressed."
This study indicates that while genetic alterations from LINE-1 movement do occur in cancers, their impact on 3D genome architecture—which supports gene expression relevant for tumor progression—is likely much more significant and widespread among various types of cancer cells examined by researchers.
"In the future, we hope to understand, on a broader scale, how these abundant genomic repetitive elements contribute to cancer phenotypes, including therapy response," said Xu.
