D&D-seq Maps DNA-Binding Proteins in Single Cells
D&D-seq is a new biotechnology that allows scientists to map protein-DNA interactions at the single-cell level by docking a DNA-editing enzyme to specific regulatory proteins. Developed by researchers at Weill Cornell Medicine and the New York Genome Center, the method overcomes previous technical limitations in mapping the “regulome,” offering a clearer view of how gene activity is controlled in health and disease.
How does D&D-seq change gene regulation research?
D&D-seq simplifies the way researchers observe the “regulome”—the complex network of proteins that switch genes on or off. According to a study published in Cell on June 4, the technique uses antibodies to guide a deaminase enzyme to a target protein. When that protein touches DNA, the enzyme leaves a permanent mark, creating a record of the interaction that can be captured through standard sequencing.
Previous methods, such as ChIP-seq, often struggled with “transient” binding events where proteins interact with DNA for only a fraction of a second. Because D&D-seq uses a marking enzyme, it catches these fleeting moments that older tools frequently missed. This is particularly important because many disease-associated mutations are located exactly where these transcription factors bind to DNA.
The “D&D” in D&D-seq stands for the docking of a protein of interest to a deaminase enzyme, turning DNA into a biological tape recorder for protein activity.
Why is single-cell “multi-omics” the next frontier?
Modern biology is moving away from bulk analysis, where thousands of cells are crushed together, losing individual variation. Single-cell multi-omics allows researchers to look at the genome (DNA), the transcriptome (gene activity), and the proteome (protein populations) within a single cell simultaneously.
Dr. Dan Landau, a professor at Weill Cornell Medicine, notes that research has been stalled by a lack of tools that can map these interactions in single cells. D&D-seq is designed to fit directly into existing high-throughput workflows. By seeing how a specific mutation in a leukemia patient changes the binding of a transcription factor, researchers can identify exactly which “switches” in the cell are broken.
How will this technology impact future disease treatments?
We are entering an era where transcription factors are becoming primary targets for drug development. Currently, many cancer therapies focus on blocking enzymes, but targeting the regulators that control gene expression could lead to more precise, less toxic treatments.
According to Dr. Ivan Raimondi, a senior molecular biologist at the Landau Lab, the ability to exploit DNA as a storage medium for this information is a shift in how we approach precision medicine. As researchers map these regulatory sites, they can better predict how a patient’s unique genetic makeup will respond to specific therapeutic interventions. This moves the industry closer to truly personalized medicine, where the “regulatory map” of a patient’s tumor guides the choice of therapy.
When comparing D&D-seq to older chromatin-mapping techniques, look for its compatibility with “multi-omics” workflows; the ability to gather regulatory data alongside gene expression in the same cell is what differentiates it from legacy methods.
Frequently Asked Questions
What is the main advantage of D&D-seq over older methods?
D&D-seq is uniquely compatible with single-cell multi-omics workflows and is highly sensitive to weak or transient protein-DNA binding events that traditional methods often fail to detect.
What does the “regulome” refer to?
The regulome encompasses the transcription factors and regulatory proteins that bind to DNA to turn genes on or off, acting as the control system for cellular function.
Can D&D-seq be used on patient samples?
Yes. The study demonstrated that the technology can be used on primary cells, such as blood cells taken from patients, to map how mutations alter gene regulation.
Where was this research published?
The findings were published in the June 4 issue of the journal Cell (doi: 10.1016/j.cell.2026.05.014).
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