Scientists at Weill Cornell Medicine and the New York Genome Center have developed a breakthrough technology that allows researchers to see, inside individual cells, exactly where transcription factors and other regulatory proteins bind to DNA—a capability that has eluded biologists until now. Called D&D-seq, the method uses antibodies to guide a DNA-editing enzyme to a target protein, leaving behind a detectable mark wherever that protein touches DNA, even in fleeting moments of interaction.
The work, published in Cell, arrives at a critical moment in medicine. Transcription factors—the master switches that turn genes "on" or "off"—have long been known to be crucial to both health and disease. A large proportion of disease-risk hotspots identified in genetics studies sit directly at transcription factor binding sites. Yet mapping these binding events in actual patient cells has been technically limited. Existing methods struggle with weak or transient interactions and don't integrate well with other tools scientists use to study cells, making it hard to see the complete picture of how genes are regulated.
"A lot of research has been held back because we didn't have the right tools for mapping DNA-protein interactions in single cells; and now that we have such a tool there is enormous excitement—it's really a foundational technological advance," said Dr. Dan Landau, the Bibliowicz Family Professor of Medicine at Weill Cornell and a core faculty member of the New York Genome Center. Landau co-led the work alongside Dr. Ivan Raimondi, senior molecular biologist and research innovation director in the Landau Lab, with Wei-Yu Chi and Dr. Sang-Ho Yoon as co-first authors.
The elegance of D&D-seq lies in how it exploits DNA's own information-storing power. When a researcher's target protein binds to DNA—even briefly—the tethered deaminase enzyme leaves a chemical mark. Sequencing later reveals exactly where those marks accumulated, creating a precise map of binding sites. "DNA is a marvelous molecule for recording and storing information, and we are exploiting this property to our advantage," Dr. Raimondi explained.
The team demonstrated the method's potential by mapping binding sites of several transcription factors and chromatin remodeling proteins, which influence genes by locally opening or closing DNA's twisted structure. In one compelling application, they compared blood cells with and without a common leukemia mutation, showing in detail how that single genetic change reshapes where a key transcription factor binds—a window into disease mechanisms that could ultimately guide treatment.
What sets D&D-seq apart is its compatibility with existing laboratory workflows. Single-cell multi-omics—the analysis of genomes, transcriptomes, proteomes, and regulatory layers simultaneously—is already transforming how scientists understand cells in health and disease. D&D-seq plugs directly into these platforms. "D&D-seq is platform-agnostic—it's basically a plug-and-play feature that you can add to existing platforms to get more information from your experiments," Dr. Raimondi said.
As medicine enters an era where transcription factors and gene regulators become increasingly important as drug targets, this foundational advance in seeing them at work promises to reshape how therapies are developed and evaluated. Landau, an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, anticipates widespread adoption of the technology. Though still a work in progress with many improvements planned, D&D-seq has already begun to unlock capabilities that researchers have long sought.