A new technique will allow scientists to map the DNA-binding sites of transcription factors and other regulatory proteins that control gene activity in single cells, according to a study led by researchers at Weill Cornell Medical Institute and the New York Genome Center. This technique offers important advantages over currently used methods and is expected to be a powerful addition to biologists’ toolkits for studying cells in health and disease.
The new method, called D&D-seq, uses antibodies to bring a DNA-editing enzyme close to a target protein, allowing researchers to record where the protein interacts with DNA. A study describing the technology, published June 4 in the journal Cell, showed that it overcomes important technical shortcomings of current methods of mapping protein-DNA interactions and is the first method of its kind that can be easily incorporated into high-throughput, single-cell “multi-omics” workflows.
“A lot of research has been put off because we didn’t have the right tools to map DNA-protein interactions within single cells, and we’re very excited that we now have such tools. This is a truly fundamental technological advance,” said study co-author Dr. Dan Landau. Dr. Dan Landau is the Bibliowicz Family Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell. Dr. Landau is also a core faculty member at the New York Genome Center.
The study’s other co-senior author is Dr. Ivan Raimondi, senior molecular biologist and director of research and innovation at the Landau Institute. Wei-Yu Qi, a doctoral candidate in the Weill Cornell School of Medicine, and Dr. Sang-Ho Yun, a medical postdoctoral fellow in the Landau lab, are co-lead authors of the paper.
Multi-omics refers to analysis that combines information from different layers within a cell, such as DNA sequence (genome), gene activity patterns (transcriptome), and protein populations (proteome). Sometimes called the regulationome, it includes transcription factors and other proteins that bind to DNA and turn genes “on” or “off.”
These regulatory proteins are known to be of great importance in biology. The majority of disease risk hotspots identified in genetic studies reside at transcription factor binding sites. However, there have been significant limitations in the tools available to map actual transcription factor DNA binding events in cells, including primary cells taken from patients. These include relative insensitivity to weak or transient binding events, and incompatibility with other standard multi-omics tools, incompatibilities that can make it difficult to get a complete picture of how genes or gene networks are regulated.
The origin of the name D&D-seq is Docking the protein of interest Deaminase enzyme followed by normal Sequencing. Even transient binding of deaminase-binding proteins to DNA leaves marks that can be detected in sequence data.
DNA is an amazing molecule for recording and storing information, and we use this property to our advantage. ”
Dr. Ivan Raimondi, Senior Molecular Biologist
The researchers demonstrated the potential of D&D-seq by using it to map binding sites for several transcription factors as well as chromatin remodeling proteins that influence gene activity by locally opening and closing twisted structures in DNA. The demonstration included mapping the DNA binding sites of key transcription factors in blood cells and comparing cells with and without common leukemia mutations, allowing researchers to closely observe how mutations alter transcription factor binding.
“We are entering an era of medicine in which transcription factors and other gene activity regulators are increasingly therapeutic targets,” said Dr. Landau, who is also an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “This type of technology should play an important role in the development and evaluation of such treatments.”
The researchers showed that D&D-seq, although a work in progress with many improvements planned, is already available in standard single-cell multi-omics platforms, allowing the mapping of gene activity patterns, whole genome sequences, and DNA-protein interactions in parallel with associated reads of other “omics” layers within individual cells.
“D&D-seq is platform independent; it is essentially a plug-and-play feature that you can add to your existing platform to get more information from your experiments,” said Dr. Raimondi.
Doctors. Landau and Raimondi expect D&D-seq to be widely adopted for multi-omics-based research. They have already trained researchers in other labs to use it and aim to commercialize the approach, Landau said.
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Reference magazines:
Chee, W.-Y. Others. (2026). Single-cell mapping of regulatory DNA-protein interactions. cell. DOI: 10.1016/j.cell.2026.05.014. https://www.cell.com/cell/fulltext/S0092-8674(26)00573-8
