The knot-like i-motif structure protruding from DNA’s double helix has been mapped in 50,000 locations in the human genome, concentrated in key functional areas including regions that control gene activity. (Credit: Garvan Institute)
DARLINGHURST, Australia — The human genome has been hiding a secret: it’s full of knots. A new study has mapped over 50,000 regions where DNA folds into complex structures called i-motifs, potentially revealing a new dimension of genetic regulation. This discovery could revolutionize our understanding of how genes are regulated and potentially lead to new approaches to treating diseases.
For decades, scientists have known that DNA typically exists as a double helix, the iconic twisted ladder structure famously described by Watson and Crick. However, this new research reveals that certain sections of our genetic code can adopt a more exotic shape, folding in on themselves to create four-stranded knots.
These i-motif structures, named for their unusual folding pattern, were once thought to be laboratory curiosities that couldn’t exist in living cells. The conventional wisdom held that they required acidic conditions incompatible with life. However, recent advances have shown that i-motifs can form under physiological conditions, and now this study demonstrates just how prevalent they are throughout the human genome.
Led by researchers at the Garvan Institute of Medical Research in Australia, the team developed a novel method to map i-motif structures across the entire human genome. They used a specially designed antibody that specifically recognizes and binds to i-motifs, allowing them to fish out these structures from purified human DNA.
The results, published in The EMBO Journal, were striking. The researchers identified over 50,000 regions capable of forming i-motifs across DNA samples from three different human cell lines. These structures were found throughout the genome, in various parts of genes and the spaces between them.
“That’s a remarkably high number for a DNA structure whose existence in cells was once considered controversial,” says senior author Daniel Christ, Head of the Antibody Therapeutics Lab and Director of the Centre for Targeted Therapy at Garvan, in a statement. “Our findings confirm that i-motifs are not just laboratory curiosities but widespread – and likely to play key roles in genomic function.”
What do these enigmatic DNA origami structures actually do?
The study provides compelling evidence that i-motifs play important roles in regulating gene activity. They tend to be located near the start sites of genes and are particularly abundant in genes that become active during the early stages of the cell cycle when cells prepare to divide.
This association with gene regulation is further supported by the fact that i-motifs often overlap with other known regulatory elements in the genome. For example, they frequently occur near another type of unusual DNA structure called G-quadruplexes, which have already been implicated in controlling gene expression.
Understanding how i-motifs contribute to gene regulation could provide new insights into fundamental biological processes and disease mechanisms. It might also open up new avenues for drug development, as molecules that target or manipulate i-motifs could potentially be used to control gene activity in therapeutic contexts.
“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,” says study co-author Sarah Kummerfeld, Chief Scientific Officer at Garvan. “It might be possible to design drugs that target i-motifs to influence gene expression, which could expand current treatment options.”
The research also highlights the dynamic nature of our genetic material. Far from being a static blueprint, DNA appears to be a shape-shifting molecule capable of adopting different conformations to fine-tune its function. This adds another layer of complexity to the already intricate dance of genes and proteins that orchestrate life.
As with any major scientific advance, this discovery raises as many questions as it answers. How exactly do i-motifs form and resolve in living cells? What proteins interact with them? How do they change in different cell types or disease states? These questions will undoubtedly drive future research in this exciting new field. The discovery of widespread i-motifs in human DNA opens up a new chapter in our understanding of genetics and may ultimately lead to novel approaches for diagnosing and treating a wide range of diseases.
Paper Summary
Methodology
The researchers used a clever technique to map i-motifs across the human genome. They started with DNA extracted from three different human cell lines, breaking it into small fragments. Then, they used a special antibody (called iMab) that specifically recognizes i-motif structures. This antibody acted like a fishing hook, allowing them to pull out DNA fragments containing i-motifs.
These fragments were then sequenced to determine their exact location in the genome. To validate their findings, the team synthesized some of the identified DNA sequences and used biophysical techniques to confirm that they indeed formed i-motifs under various conditions.
Key Results
The study identified over 50,000 regions capable of forming i-motifs across the genomes of three different cell lines. These structures were found throughout the genome, including in gene regulatory regions, introns (non-coding sections within genes), and intergenic spaces.
Importantly, i-motifs were often located near the start sites of genes and were particularly abundant in genes that become active during the early stages of the cell cycle. The researchers also observed a significant overlap between i-motif locations and other known regulatory elements, such as G-quadruplexes.
Study Limitations
While groundbreaking, this study has some limitations. The 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 of a living cell.
Additionally, the study focused on just three cell lines, which may not capture the full diversity of i-motif patterns across different cell types or physiological states. The researchers also note that their method might not detect all possible i-motif structures, particularly those that are less stable or form under different conditions.
Discussion & Takeaways
This research provides strong evidence that i-motif structures are a common and likely important feature of the human genome. The widespread distribution of i-motifs and their association with gene regulatory regions suggest they play a significant role in controlling gene expression. This could have far-reaching implications for our understanding of gene regulation, cellular processes, and disease mechanisms.
The study also highlights the dynamic nature of DNA, showing that our genetic material is capable of adopting complex three-dimensional structures beyond the classic double helix. These findings open up new avenues for research into DNA structure and function and may ultimately lead to novel therapeutic approaches that target or manipulate i-motifs to control gene activity.
Funding & Disclosures
The study was funded by the National Health and Medical Research Council. The researchers declared no competing interests related to this work. The paper acknowledges the use of services and facilities from the Australian Genome Research Facility and the Children’s Medical Research Institute.
This is one reason way, way, back decades ago, they should never have allowed “genetic engineering” of the stuff we eat. Back at that time we know practically nothing about the complexity we understand today.
There is a fascinating book called “Altered Genes, Twisted Truths” by Steven Druker that goes deep into the genetic engineering industry, and by implication all of American industry. One comment from one of the directors of I think it was the FDA is that if Americans want to maintain our scientific lead in the world we have to get used to the idea that we are guinea pigs for large scale experimentation such as this.
This attitude justifies industries hiding whether their products are genetically engineered.
Early “genetic engineering” used to be carried out by taking seeds or DNA material and bombarding them with chunks of selected genes to see if those genes would implant into the plants DNA. They plant the seeds and then examine the results and keep ones they liked – never knowing what was really inside their genomes. Sometimes there were very toxic results hidden that are not immediately perceivable. See the L-tryptophan by Showadenko which resulted in deaths across the world. hardly engineering, more like gambling, and with random lives.