The so-called i-motifs are knot-like DNA structures formed in the nuclei of human cells and believed to provide critical genomic regulation. In new research, scientists from the Garvan Institute of Medical Research and elswhere used immunoprecipitation and next-generation sequencing to identify i-motif structures in human DNA.
Peña Martinez et al. observed a total of 53,000 i-motifs among three human cells lines: MCF7, U2OS, HEK293T. Image credit: Peña Martinez et al., doi: 10.1038/s44318-024-00210-5.
I-motifs are DNA structures that differ from the iconic 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.
In 2018, scientists at the Garvan Institute of Medical Research were the first to directly visualize i-motifs inside living human cells using a new antibody tool they developed to recognise and attach to i-motifs.
The new research builds on those findings by deploying this antibody to identify i-motif locations across the entire 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 Garvan Institute of Medical Research’s Professor Daniel Christ, senior author of the study.
“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.”
The researchers found that i-motifs are not randomly scattered but concentrated in key functional areas of the genome, including regions that control gene activity.
“We discovered that i-motifs are associated with genes that are highly active during specific times in the cell cycle,” said first author Dr. Cristian David Peña Martinez, also from the Garvan Institute of Medical Research.
“This suggests they play a dynamic role in regulating gene activity.”
“We also found that i-motifs form in the promoter region of oncogenes, for instance 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.”
“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,” said Dr. Sarah Kummerfeld, a co-author of the study and a researcher at the Garvan Institute of Medical Research.
“It might be possible to design drugs that target i-motifs to influence gene expression, which could expand current treatment options.”
The team’s results were published in the EMBO Journal.
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Cristian David Peña Martinez et al. Human genomic DNA is widely interspersed with i-motif structures. EMBO J, published online August 29, 2024; doi: 10.1038/s44318-024-00210-5
Source : Breaking Science News