Plate Nº 82 · recorded November 12, 2026
Biology & EvolutionReported finding
New Yale Method Maps DNA Folding and Epigenetic Marks in Single Cells
Yale's Epi-PHR method profiles hundreds of genetic sites in single cells, mapping epigenetic marks and DNA's 3D folding simultaneously — something no prior technique could do.
By James Calloway3 min read689 words
In brief
- Epi-PHR, published in Nature Methods in 2026, profiles hundreds of genetic sites in a single cell while preserving DNA's 3D folding.
- The method was developed by Siyuan "Steven" Wang's lab at Yale School of Medicine, adapting a 2015 Swedish protein-interaction technique.
- Two hairpin-shaped molecules carry an inactivated fluorescent tag that glows when an epigenetic mark sits directly on a gene.
- The team tested Epi-PHR on a hippocampus tissue slice, revealing a gradient of epigenetic and 3D structures across neurons.
- Paper: Yanbo Chen et al., Nature Methods (2026), DOI: 10.1038/s41592-026-03253-0.
A single cell can now have hundreds of genetic sites profiled at once — with both its DNA folding and its epigenetic marks intact. That's the claim behind Epi-PHR, a new method developed at Yale School of Medicine and published in Nature Methods in 2026, and it fills a gap that has frustrated geneticists for years.
The problem is straightforward, if technical. Which genes a cell actually uses depends on two things: how DNA is folded into three-dimensional structures inside the nucleus, and epigenetic marks — chemical modifications on DNA and its associated proteins that switch genes on or off. Most existing methods can't measure both at once.
The current state-of-the-art technique for mapping epigenetic marks in single cells destroys DNA folding in the process. Other approaches that capture 3D structure can't resolve changes at the single-cell or single-gene level. So researchers wanting to see how chemical modifications overlay physical structure have been stuck choosing one or the other.
How does the technique actually work?
The Yale team, led by Siyuan "Steven" Wang, associate professor of genetics, borrowed an idea. They adapted a technique developed by researchers in Sweden in 2015 for studying protein-protein interactions.
Epi-PHR uses two hairpin-shaped molecules, each engineered to bind either an epigenetic mark or a gene of interest. One molecule carries an inactivated fluorescent tag. When the two hairpins sit next to each other — say, when an epigenetic modification sits directly on top of a gene — the hairpin opens and the tag glows.
Glow means contact. No glow means no contact. It's proximity made visible, and it lets researchers map the epigenome and the 3D genome in the same cell at the same time.
Wang says the method "offers unprecedented capacity for people that have specific questions about particular genes of interest," and adds: "If you want to know at a single-cell level what epigenetic mark is present at a gene, and map its 3D folding, this is the best technique."
Why does the pairing matter?
All cells in an organism carry identical DNA. What differs is access. Cells pack most of their DNA by winding it around proteins called histones and folding those complexes into higher-order 3D structures, keeping only the necessary genes available for action.
Epigenetic marks fine-tune that access further, turning genes on and off without changing the underlying sequence. Together, the fold and the marks decide what genetic information a cell uses — and, by extension, what that cell does.
"The epigenome and 3D genome affect essentially all genomic functions," Wang explains, including transcription (the first step of gene reading), DNA replication and DNA damage repair. Epigenetic changes appear to drive many cancers and developmental diseases, which is why a tool that sees both layers together matters.
What does this change for medicine?
Right now, mostly research. The Yale team demonstrated Epi-PHR on hundreds of genetic sites in single cells, detecting multiple epigenetic marks simultaneously. They also applied it to real tissue — a slice of the hippocampus, the brain's memory hub — where it revealed a gradient of epigenetic and 3D structures across neurons and neighboring cells.
That tissue result is the quiet headline here. Methods that work in isolated cells often fail in intact tissue, where cell types are mixed and structure matters. Epi-PHR held up.
The method could, one day, help researchers develop better treatments for genetic conditions. That day is not today. The paper demonstrates capability, not clinical payoff, and "best technique" is Wang's own assessment of a method his lab built. Independent labs will need to reproduce the results, and the profiling of hundreds of sites remains modest against a genome of roughly three billion base pairs.
Still, for a field that has long needed to study the 3D genome together with the epigenome — as Wang puts it, "a long-standing need" — Epi-PHR offers a first practical answer.
The paper is published as Yanbo Chen et al., "Nondisruptive 3D profiling of combinations of epigenetic marks in single cells," Nature Methods (2026), DOI: 10.1038/s41592-026-03253-0.
via phys.org/rss-feed/ (Source)
More from James Calloway
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Staff writer covering regulation, policy and their impact on general science news at SciBeat.
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