Innovative study of DNA’s hidden structures may open up new approaches for treatment and diagnosis of diseases, including cancer.
A groundbreaking investigation into the concealed configurations of DNA might pave the way for fresh strategies in treating and diagnosing illnesses, such as cancer.
While DNA is widely recognized for its iconic double helix form, researchers at the Garvan Institute of Medical Research have uncovered the presence of over 50,000 unique ‘knot’-like DNA formations, known as i-motifs, within the human genome.
Todays’ publication in The EMBO Journal presents the first detailed map of these special DNA structures, highlighting their possible involvement in regulating genes that are associated with various diseases.
In a groundbreaking study conducted in 2018, Garvan scientists became the first to visualize i-motifs within living human cells by utilizing a novel antibody tool that recognizes and binds to these structures. This current study builds on those earlier findings by using this antibody to pinpoint i-motif locations throughout the entire genome.
Senior author Professor Daniel Christ, Head of the Antibody Therapeutics Lab and Director of the Centre for Targeted Therapy at Garvan, explains, “Through this research, we have mapped over 50,000 sites of i-motifs in the human genome, found across all three cell types we studied. This is a remarkably high figure for a DNA structure previously considered controversial. Our results demonstrate that i-motifs are not merely lab anomalies but are widespread and likely crucial for genomic functions.”
Intriguing DNA i-motifs may play an active role in gene function
I-motifs take on a different form than the well-known double helix. They emerge when sequences of cytosine in the same DNA strand pair up, resulting in a four-stranded twisted structure that extends outward from the double helix.
The study revealed that i-motifs are not randomly distributed but are primarily located in essential functional regions of the genome, particularly those that regulate gene expression.
“We found that i-motifs are linked to genes that are especially active at certain stages of the cell cycle, indicating they might play a key role in regulating gene expression,” notes Cristian David Peña Martinez, a research officer in the Antibody Therapeutics Lab and lead author of the paper.
“We’ve also discovered that i-motifs form in the promoter region of oncogenes, such as the MYC oncogene, which is known to be one of the most challenging targets for cancer treatments. This opens up exciting possibilities for targeting disease-related genes through the structure of i-motifs,” he adds.
I-motifs offer potential for innovative therapies and diagnostics
“Given the widespread occurrence of i-motifs near these crucial areas associated with hard-to-treat cancers, we are looking at new avenues for diagnostics and therapies. It’s conceivable that we could develop drugs aimed at i-motifs to influence gene expression, potentially broadening treatment options,” says Associate Professor Sarah Kummerfeld, Chief Scientific Officer at Garvan and a co-author of the study.
Professor Christ emphasizes that identifying i-motifs was made possible by Garvan’s top-tier capabilities in antibody development and genomic studies. “This research exemplifies how foundational research and technological advancements can collaborate to produce groundbreaking discoveries,” he remarks.
This study received support from the National Health and Medical Research Council.
Professor Daniel Christ is also a Conjoint Professor at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney. Associate Professor Sarah Kummerfeld holds a Conjoint Associate Professor position at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.
