LINE-1 Retrotransposons Reshape Cancer Genome Architecture

Scientists at St. Jude Children's Research Hospital have revealed previously unappreciated roles for the retrotransposon LINE-1 in shaping the cancer genome structure and regulation. Retrotransposons are mobile DNA pieces, comprising much of the human genome. These so-called "jumping genes" can copy and insert themselves throughout the genome, contributing to various diseases, including cancer. The researchers identified a new class of highly interactive LINE-1 loci (genome regions) that modulate cancer gene expression by altering three-dimensional (3D) genome architecture. The findings, which have implications for the understanding of cancer development, were published today in Cancer Discovery, a journal of the American Association for Cancer Research.

LINE-1 is the most abundant retrotransposon and can uniquely move itself, a process usually suppressed in normal cells but often inexplicably elevated in cancer cells. Due to their ability to cause genetic alterations, LINE-1 retrotransposons have been implicated as major drivers of cancer, but how they accomplish this has been poorly understood.

The conundrum is that if this is true, we should see many more oncogenic mutations due to these events. 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."

Jian Xu, PhD, corresponding author, St. Jude Department of Pathology

To understand how dysregulated LINE-1 elements contribute to cancer, Xu and his team used an interdisciplinary approach to investigate the roles of reactivated LINE-1 gene products in tumor biology. They developed a sequencing-based chromatin structure assay capable of reading long lengths of complex, repetitive retrotransposon regions, providing unprecedented insight into the 3D interactions formed by LINE-1. Their results uncovered previously unrecognized functions of LINE-1 in cancer.

LINE-1 Locus-Specific Transcription Regulates Genome Architecture and Cancer Gene Expression

The researchers found that RNAs produced by evolutionarily young LINE-1 loci remain largely associated with chromatin, where they promote genome structural changes to bring chromatin regions that are usually far apart together. These structural changes allow for the high-level expression of genes that drive cancer cell proliferation.

"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," explains 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."

These structural changes show that while LINE-1 activity can promote cancer through genetic alterations, the much more prevalent mechanism appears to be nongenetic through reconfiguration of 3D genome architecture to support cancer gene expression. Further, researchers found that this phenomenon is widespread; almost all the cancer cells they looked at have LINE-1 reactivation and can form these HILL structures.

The research demonstrates the unexpected contributions of LINE-1 retrotransposons to cancer gene expression. "In the future, we hope to understand, on a broader scale, how these abundant genomic repetitive elements contribute to cancer phenotypes, including therapy response," says Xu.