When we learn about human genetics in high school biology class, one of the most basic things we learn about is the DNA double helix, the twisting ladder-shaped structure that holds our genetic code. But scientists have long suspected there’s another type of DNA that looks quite different from the famous Watson-Crick model. They theorized that it’s knot-shaped, though they’d never observed it in a living cell … until now.

In a paper published Monday in the journal Nature Chemistry, a team of researchers describe their evidence for the existence and possible function of this knotty DNA, called “human telomeric i-motif.” To identify the i-motif DNA, the researchers, led by first author Mahdi Zeraati a Ph.D. student at the Garvan Institute of Medical Research in Sydney, Australia, developed an antibody that would bind to the elusive DNA and allow them to capture images of it with the help of immunofluorescent staining. They suspect that the i-shaped DNA, which had previously only been observed in lab conditions very different from those in a living cell, regulates some genetic functions.

i-motif DNA
Researchers observed the i-motif DNA blink in and out, suggesting that it's regulating a cell function.

“We provide the first direct evidence for the presence of i-motif structures in the nuclei of human cells,” the study’s authors write, as this is the first time anyone has observed the i-motif DNA, except for in lab conditions that don’t represent actual conditions in a living cell. The fact that scientists finally observed this different form of DNA in human cells is a pretty big deal, but it’s actually even more than just a different shape. It seems to play by different rules than double-helix DNA, too. It employs nucleotides — the basic A, G, T, and C units that compose DNA — a lot differently than helical DNA does.

“The i-motif is a four-stranded ‘knot’ of DNA,” Marcel Dinger, Ph.D., an associate professor at Garvan and one of the study’s authors, explained in a statement released Monday. “In the knot structure, C letters on the same strand of DNA bind to each other — so this is very different from a double helix, where ‘letters’ on opposite strands recognize each other, and where Cs bind to Gs.”

This paper represents a very early stage of figuring out what the i-motif DNA actually does in human cells. One idea the team has is that the i-motif DNA regulates some cell function, as indicated by the fact that it seemed to blink on and off in their observations. “We think the coming and going of the i-motifs is a clue to what they do,” said Zeraati. “It seems likely that they are there to help switch genes on or off, and to affect whether a gene is actively read or not.”

Future studies of the i-motif DNA will be necessary to figure out exactly what its role is, but this paper sets the groundwork for observing it, which is a significant step toward unlocking its mysteries.