New Fluorescent Probes Let Scientists Watch DNA Fold Inside Living Cells

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona, the City University of Hong Kong, and the Guangdong Provincial People's Hospital (Southern Medical University) have designed fluorescent probes called HoTs that can enter living cells and bind to DNA, revealing how it is folded and how it moves at exceptionally fine scales. The work, described in the journal Molecular Cell, could eventually help doctors read DNA packaging as a clue for disease diagnosis and treatment.

The dyes are engineered to blink intermittently rather than glow continuously, which lets a microscope pinpoint each probe's location and combine thousands of snapshots into a far sharper image. Using a technique called STORM, the researchers visualized DNA inside living human skin cells and HeLa cancer cells at a resolution of 20 nanometers. In chemically preserved cells, a second technique called MINFLUX located individual dye molecules to within 3 nanometers, close to the roughly 2-nanometer width of the DNA double helix itself.

When the team tested the probes on wax-preserved bowel tissue from three cancer patients, DNA in the tumors appeared noticeably looser and more spread out than in healthy tissue right beside it. Doctors currently assess such biopsies by eye using a staining technique more than a century old; the researchers say the new approach could eventually add the three-dimensional arrangement of DNA as another clue in cancer diagnosis.

The team also trained an AI program called AINU on the new living-cell images and found it could distinguish skin cells from stem cells with 96 to 98 percent accuracy, even though the two cell types carry identical DNA packaged differently. The probes worked outside human cells too, in zebrafish eye tissue, where cells are thought to loosen their DNA as they regenerate a damaged retina.