Genetic mystery: 50,000 DNA "knots" found in the human genome

DNA is famously known for its double helix structure, but the human genome also contains more than 50,000 unusual knot-like DNA structures known as i-motifs, according to a team of experts at the Garvan Institute of Medical Research.

In a study published in the EMBO Journal, the scientists presented the first comprehensive map of these unique DNA structures, shedding light on their potential roles in gene regulation, particularly in relation to diseases such as cancer.

Abundance and distribution of i-motifs 

“DNA i-motif structures are formed in the nuclei of human cells and are believed to provide critical genomic regulation,” noted the study authors. 

“While the existence, abundance, and distribution of i-motif structures in human cells has been demonstrated and studied by immunofluorescent staining, and more recently NMR and CUT&Tag, the abundance and distribution of such structures in human genomic DNA have remained unclear.”

Pinpointing the mysterious DNA structures

Back in 2018, Garvan scientists achieved a breakthrough by being the first to directly visualize i-motifs within living human cells, as they detailed in the journal Nature. The team developed a novel antibody tool specifically designed to recognize and bind to i-motifs. 

The current research builds on this earlier work, utilizing the same antibody to pinpoint the locations of i-motifs throughout the entire human genome.

“In this study, we mapped more than 50,000 i-motif sites in the human genome that occur in all three of the cell types we examined,” said senior author Daniel Christ, head of the Antibody Therapeutics Lab and Director of the Centre for Targeted Therapy at Garvan. 

“That’s a remarkably high number for a DNA structure whose existence in cells was once considered controversial. Our findings confirm that i-motifs are not just laboratory curiosities but widespread – and likely to play key roles in genomic function.”

I-motifs are not randomly distributed 

I-motifs are distinctive DNA structures that differ from the well-known double helix. They form when stretches of cytosine bases on the same DNA strand pair with each other, creating a four-stranded, twisted configuration that protrudes from the double helix.

The research revealed that i-motifs are not randomly distributed. The experts discovered that they are concentrated in key functional regions of the genome, including areas that control gene activity.

The role of i-motifs in gene activity

The experts determined that the formation of the distinctive DNA structures is cell-cycle and pH dependent. “Furthermore, we provide evidence that i-motif structures are formed in regulatory regions of the human genome, including promoters and telomeric regions.” 

Study lead author Cristian David Peña Martinez, a research officer in the Antibody Therapeutics Lab, explained that i-motifs are associated with genes that are highly active during specific times in the cell cycle, which suggests they play a dynamic role in regulating gene activity.

“We also found that i-motifs form in the promoter region of oncogenes, such as the MYC oncogene, which encodes one of cancer’s most notorious ‘undruggable’ targets. This presents an exciting opportunity to target disease-linked genes through the i-motif structure,” he added.

Implications for hard-to-treat cancers 

According to study co-author Sarah Kummerfeld, an assistant professor and chief scientific officer at Garvan, the widespread presence of i-motifs near these “holy grail” sequences involved in hard-to-treat cancers opens up new possibilities for diagnostic and therapeutic approaches. 

“It might be possible to design drugs that target i-motifs to influence gene expression, which could expand current treatment options,” said Professor Kummerfeld.

Significance of the study

Professor Christ pointed out that the successful mapping of i-motifs was made possible by Garvan’s world-leading expertise in antibody development and genomics. 

“This study is an example of how fundamental research and technological innovation can come together to make paradigm-shifting discoveries,” said Professor Christ.

“Our study provides foundational knowledge and resources relating to the location and distribution of i-motifs in human genomic DNA, representing potential targets for future diagnostic and therapeutic strategies,” the authors concluded.

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