Knot-like DNA structures in human genome mapped

The structure of the double helix continues to be unravelled as scientists produce the first comprehensive map of 'knot'-like structures, called i-motifs.

Scientists at the Garvan Institute of Medical Research in Sydney, Australia, have mapped over 50,000 i-motifs – where DNA folds into complex 'twisted knot' structures – potentially revealing a new dimension of genetic regulation. This builds on work from 2018 when the same team discovered i-motifs in living cells for the first time (see BioNews 947). At that time, the team used an antibody fragment to recognise and attach to i-motifs. Now, the antibody fragment was deployed genome-wide to identify i-motif locations across the entire human genome.

'That's a remarkably high number for a DNA structure whose existence in cells was once considered controversial,' said lead author Professor Daniel Christ, head of the Antibody Therapeutics Lab and director of the Centre for Targeted Therapy at Garvan. '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 DNA structures that differ from the established double helix shape. They form when stretches of cytosine letters on the same DNA strand pair with each other, creating a four-stranded, twisted structure protruding from the double helix.

The team, who published their research in The Embo Journal, found that i-motifs are not randomly scattered, but are concentrated in key functional areas of the genome that control gene activity. Additionally, i-motifs were found to frequently co-occur near G-quadruplexes, which have been implicated in controlling gene expression. The team also found that i-motifs form in the promoter region of oncogenes, such as the MYC oncogene, which is overactive in over half of all human cancers. Currently, no drugs are able to inhibit the MYC gene because its protein structure complicates therapeutic targeting.

Together, the authors suggest, that these results solidify i-motifs' association with gene regulation.

It is of note that experiments were performed on purified DNA outside of living cells, so it's not certain how closely this reflects i-motif formation in the complex environment inside a living cell. Additionally, only three cell lines were used, thus, not all i-motif structures may have been detected.

Nonetheless, Dr Sarah Kummerfeld, chief scientific officer at Garvan and co-author of the study said: 'the widespread presence of i-motifs near these "holy grail" sequences involved in hard-to-treat cancers opens up new possibilities for new 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.'

Overall, this study reveals the dynamic nature of DNA and the findings open up new avenues for research into DNA structure and function, with the potential for novel therapeutic approaches that target or manipulate i-motifs to control gene activity.