Scientists at Weill Cornell Medicine and the New York Genome Center have unveiled a groundbreaking method called D&D-seq, capable of mapping DNA-binding proteins in single cells with unprecedented precision. Published June 4 in Cell, the technique overcomes critical limitations of existing tools, offering a platform-agnostic approach that integrates seamlessly with high-throughput single-cell multi-omics workflows. “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, co-senior author and oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
How D&D-seq Works
D&D-seq leverages antibodies to tether a DNA-editing enzyme, a deaminase, to target proteins, enabling researchers to record where these proteins interact with DNA. Unlike traditional methods like ChIP-seq or CUT&RUN, which struggle with weak or transient interactions, D&D-seq detects even fleeting binding events by converting cytosine to uracil at protein-bound sites. This creates a “molecular breadcrumb trail” that reveals regulatory patterns invisible to older techniques. “DNA is a marvelous molecule for recording and storing information, and we are exploiting this property to our advantage,” explained Dr. Ivan Raimondi, senior molecular biologist in the Landau Lab.
The method’s versatility was demonstrated by mapping transcription factors and chromatin remodeling proteins across multiple cell types. One application involved profiling CTCF binding in T cells with an IDH2 mutation linked to leukemia, exposing regulatory heterogeneity masked in population-level assays. “This kind of technology should have an important role in developing and evaluating such therapies,” Landau added, highlighting its potential for precision medicine.
Key Advantages Over Existing Tools
Traditional approaches often fail to capture the nuanced, cell-to-cell variability critical for understanding gene regulation. D&D-seq addresses this by operating at single-cell resolution while remaining compatible with standard workflows like ATAC-seq and scATAC-seq. “It’s basically a plug-and-play feature that you can add to existing platforms to get more information from your experiments,” said a researcher involved in the study. This compatibility allows scientists to pair DNA-protein interaction maps with chromatin accessibility, gene expression, and genomic variation—all within the same cell.
Another major innovation is its sensitivity to weak or transient interactions, which are often missed by bulk analysis. “Even a transient binding of the deaminase-linked protein to DNA will leave a mark that can be detected in sequencing data,” Raimondi noted. This capability could transform research into diseases where regulatory proteins play a pivotal role, such as cancer, where mutations in transcription factors are prevalent.
Expert Reactions and Implications
The technology has already sparked excitement among researchers. Dr. Sang-Ho Yoon, a postdoctoral associate in the Landau Lab, emphasized its potential to “open new avenues for understanding gene regulation at an unprecedented scale.” Meanwhile, the study’s co-first authors, Wei-Yu Chi and Yoon, highlighted its role in bridging gaps between genomic data and functional biology. “A large proportion of disease-risk hotspots identified in genetics studies lie at transcription factor binding sites,” Chi said, underscoring the method’s relevance to disease research.
The implications for medicine are profound. As transcription factors increasingly emerge as therapeutic targets, D&D-seq offers a tool to monitor how mutations, drugs, or genetic edits reshape regulatory landscapes. “We’re entering an era of medicine in which transcription factors and other gene-activity regulators will increasingly be therapeutic targets,” Landau stated. The technology’s ability to analyze primary patient cells could accelerate the development of personalized treatments, particularly in oncology.
What’s Next for D&D-seq?
While still evolving, D&D-seq’s conceptual elegance and technical flexibility have already attracted attention from the scientific community. Researchers are exploring its application in diverse fields, from immunology to neurobiology. The method’s platform-agnostic design also suggests it could be adapted for use in clinical settings, potentially revolutionizing diagnostics and treatment planning.
As the team continues refining the technique, the focus will shift to scaling its use and integrating it into broader research ecosystems. “This is just the beginning,” said Raimondi. “We’ve laid the foundation for a new era of single-cell genomics.” For now, D&D-seq stands as a testament to the power of interdisciplinary collaboration, merging molecular biology, bioinformatics, and clinical research to tackle one of the most complex challenges in modern science.
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