Researchers map 50,000 mysterious DNA ‘knots’ in the human genome

Researchers have mapped 50,000 mysterious DNA “knots” in the human genome. The innovative study of DNA’s hidden structures could open new avenues for treating and diagnosing diseases, including cancer.

DNA is well known for its double helix shape. But the human genome also contains more than 50,000 unusual knot-like DNA structures, called “i-motifs”, researchers at the Garvan Institute of Medical Research have discovered.

Published today in The EMBO Journal This is the first comprehensive map of these unique DNA structures, shedding light on their potential roles in regulating genes involved in disease.

In a landmark 2018 study, Garvan scientists were the first to directly visualize i-motifs inside living human cells using a novel antibody tool they developed to recognize and bind to i-motifs. Current research builds on these findings by deploying this antibody to identify i-motifs’ locations across the genome.

“In this study, we mapped over 50,000 i-motif sites in the human genome, present in the three cell types we examined,” said Professor Daniel Christ, lead author and Director of the Garvan Antibody Therapeutics Laboratory and Targeted Therapeutics Centre. “This is a remarkably high number for a DNA structure whose existence in cells was once considered controversial. Our results confirm that i-motifs are not just laboratory curiosities, but are widespread and likely to play key roles in genomic function.”

Curious DNA i-motifs may play dynamic role in gene activity

I-motifs are DNA structures that differ from the iconic double helix shape. They form when segments of cytosine letters on the same strand of DNA join together, creating a twisted, four-stranded structure that extends beyond the double helix.

The researchers found that the i-motifs are not randomly scattered but concentrated in key functional areas of the genome, including regions that control gene activity.

“We found that i-motifs are associated with genes that are very active at specific times in the cell cycle. This suggests that they play a dynamic role in regulating gene activity,” says Cristian David Peña Martinez, a researcher in the Antibody Therapy Laboratory and first author of the study.

“We also discovered that i-motifs are formed in the promoter region of oncogenes, for example the MYC oncogene, which encodes one of the most notorious ‘undruggable’ targets of cancer. This presents an exciting opportunity to target disease-related genes through the structure of the i-motif,” he says.

“The widespread presence of i-motifs near these ‘holy grail’ sequences implicated in hard-to-treat cancers opens up new possibilities for novel diagnostic and therapeutic approaches. It may be possible to design drugs that target i-motifs to influence gene expression, potentially expanding current treatment options,” says Associate Professor Sarah Kummerfeld, Garvan’s scientific director and co-author of the study.