A pioneering advancement in cellular biology has emerged from Weill Cornell Medicine and the New York Genome Center, introducing a transformative technique named “D&D-seq” that redefines the way scientists map DNA-protein interactions in single cells. This breakthrough addresses longstanding limitations in the study of transcription factors and regulatory proteins that orchestrate gene expression, offering unprecedented clarity and depth to molecular investigations critical to understanding health and disease.
At the heart of this novel technology lies a clever biochemical strategy: antibodies are employed to tether a DNA-editing enzyme—specifically a deaminase—to a targeted DNA-binding protein within the cell. This proximity enables the enzyme to mark the exact DNA locations where these regulatory proteins interact, effectively recording these interactions as detectable DNA sequence modifications. This approach circumvents the major technical challenges posed by traditional methods, which often suffer from insensitivity to fleeting protein-DNA contacts and poor integration with multi-layered omics analyses.
Published on June 4, 2026, in the prestigious journal Cell, the study elucidates how D&D-seq integrates seamlessly into existing high-throughput single-cell multi-omics platforms. Multi-omics refers to the simultaneous analysis of various molecular dimensions in cells—ranging from genomic sequences to transcriptomic activity and proteomic composition. Prior to this, no technique had successfully combined detailed mapping of protein-DNA interaction sites with other omics readouts within individual cells, limiting the holistic understanding of gene regulation networks.
Dr. Dan Landau, a leading figure in this research, notes the game-changing potential of D&D-seq. “We have long been hampered by the lack of precise tools to map where transcription factors bind in single cells. Now, with D&D-seq, we can visualize these crucial regulatory events with unmatched resolution,” said Dr. Landau, a professor at Weill Cornell and a core member at the New York Genome Center. His insights underscore the profound implications for studying diseases where gene regulation goes awry, such as cancer and immune disorders.
The innovation’s core mechanism, involving the targeted docking (hence the “D&D” in D&D-seq) of DNA deaminases to proteins of interest, exploits DNA’s intrinsic capacity to serve as a stable information repository. Even transient encounters between a protein and a DNA strand result in a chemical signature—deamination events—that can be captured by sequencing technologies. This subtle yet permanent mark signifies where regulatory proteins have exerted their influence, offering an accurate historical record of gene regulation dynamics within each cell.
Beyond theoretical appeal, the researchers demonstrated D&D-seq’s practical utility by mapping binding sites for an array of transcription factors as well as chromatin remodelers. Chromatin remodeling proteins modulate the accessibility of DNA by altering its packaging, thereby controlling gene expression landscapes. One compelling application highlighted in their work involved comparing normal blood cells with counterparts harboring a common leukemia-related mutation. D&D-seq revealed detailed changes in transcription factor binding profiles, providing mechanistic clues into how mutations may dysregulate gene networks and drive disease progression.
This capability brings a new dimension to precision medicine. Transcription factors and their associated regulatory proteins are increasingly recognized as therapeutic targets, but the development and assessment of such interventions have been hindered by incomplete knowledge of their in vivo DNA interactions. Through D&D-seq, researchers and clinicians can gain vital insights into target occupancy and off-target effects, accelerating drug development pipelines and improving clinical outcomes.
Importantly, the technology is designed to be platform-agnostic and user-friendly, functioning as a modular “plug-and-play” extension that can be incorporated into diverse experimental setups without overhauling existing workflows. This characteristic not only democratizes access but also fosters rapid adoption across research groups worldwide, further propelling innovation in genomics and molecular diagnostics.
While D&D-seq is still evolving, with future refinements underway, its current form already bridges key gaps in the toolkit for epigenomic research. By enabling parallel measurement of DNA-protein interactions alongside genomic sequences, transcriptomes, and proteomes within the same single cell, it facilitates integrative analyses that can unravel complex biological processes with newfound precision and scale.
The collaborative project was helmed by Drs. Dan Landau and Ivan Raimondi, whose leadership and vision have been instrumental in pushing the boundaries of single-cell biology. They are actively training scientists globally and pursuing commercialization of this technology, reinforcing its anticipated widespread impact on biomedical research and therapeutic innovation.
The development of D&D-seq was supported by extensive funding from major U.S. health agencies including the National Heart Lung and Blood Institute, the National Cancer Institute, and the National Human Genome Research Institute. Philanthropic contributors such as the MacMillan Family Foundation have also played vital roles in enabling these breakthroughs at the intersection of genomics, molecular biology, and computational sciences.
This new frontier in precision cellular mapping signifies a paradigm shift, offering researchers an unprecedented lens into the dynamic choreography of gene regulation at a single-cell level. As the science community embraces D&D-seq, it promises to ignite discoveries that will deepen our molecular understanding and catalyze novel therapies for human diseases.
Subject of Research: Mapping DNA-protein interactions at single-cell resolution using a novel sequencing technology.
Article Title: Unlocking Single-Cell DNA-Protein Interactions with D&D-seq: A Next-Generation Multi-Omics Tool
News Publication Date: 4 June 2026
Web References: Not provided
References: Published in Cell, June 4, 2026
Image Credits: Not provided
Keywords
DNA binding proteins, single-cell technologies, transcription factors, gene regulation, multi-omics, chromatin remodeling, DNA deaminase, genomic sequencing, precision medicine, leukemia, molecular biology, epigenetics
Tags: advancements in cellular molecular investigationsantibody-tethered DNA-editing enzyme methodD&D-seq technique in molecular biologyDNA deaminase enzyme in cell biologygene expression regulation at single-cell levelhigh-throughput single-cell genomicsmulti-layered omics analysis in single cellsprecision mapping of protein-DNA contactsregulatory protein DNA interaction detectionsingle-cell DNA-protein interaction mappingsingle-cell multi-omics integrationtranscription factor binding analysis
