A groundbreaking molecular tool, known as SCOPE, has been developed by researchers at Weill Cornell Medicine, offering an unprecedented capacity to pinpoint proteins that regulate gene activity within cells. This innovative technology is poised to revolutionize fundamental biological research and disease studies by providing detailed insights into the protein-DNA interactions that govern gene expression.
Gene activity is regulated by proteins that interact with specific DNA regions, acting as molecular switches that can activate, enhance, suppress, or silence genes. Traditionally, the identification and study of these DNA-binding proteins have been hampered by technical limitations, chiefly the difficulty of capturing proteins that bind transiently or weakly to chromatin. The SCOPE system overcomes this challenge by enabling scientists to target an exact location within the genome and capture any proteins in close proximity for subsequent analysis.
Central to SCOPE’s function are two key components: a guide RNA and a photo-reactive amino acid. The guide RNA is customizable and directs the system to virtually any desired genomic site. Coupled with this, a uniquely engineered protein incorporates an amino acid that remains inert under normal conditions but becomes highly reactive when exposed to ultraviolet (UV) light, facilitating the formation of covalent bonds with nearby DNA-binding proteins. This photo-crosslinking capability enables precise and durable capture of proteins localized at targeted DNA regions.
The amino acid integrated into SCOPE is a non-natural residue derived from archaea, a class of ancient single-celled microorganisms evolutionarily distinct from mammals and bacteria. This biological divergence renders the amino acid essentially unreactive within mammalian cells until activated by UV illumination, ensuring minimal nonspecific interactions and thereby dramatically enhancing the sensitivity and specificity of protein capture.
Upon UV exposure, the amino acid crosslinks to proteins within molecular reach, creating stable complexes that researchers can isolate using established biochemical methods. These bound proteins are subsequently identified via mass spectrometry, a powerful analytical technique that deciphers protein composition and structure with exceptional precision. This workflow facilitates an accurate map of protein occupancy at any selected genomic locus.
SCOPE functions within live cells, allowing it to assemble and operate intracellularly. This dynamic intracellular operation provides a real-time representation of protein-DNA interactions, crucial for understanding regulatory mechanisms that occur in the native cellular context. The versatility of SCOPE permits its use across various cell types, including stem cells, expanding its relevance to diverse biological and medical fields.
To validate their method, the research team applied SCOPE to human embryonic stem cells, focusing on specific genes characterized by complex regulatory mechanisms. They elucidated the roles of three proteins, identifying two that preserve the cells’ pluripotency, maintaining their undifferentiated state, while a third protein was found to drive differentiation towards mature cell types. These insights illuminate the intricate control systems governing human development and cellular identity.
Beyond fundamental biology, the developers of SCOPE anticipate broad applications in disease research. Plans are underway to deploy this technology to investigate gene-regulating proteins in pathological contexts, such as disruptions in cardiomyocyte function associated with arrhythmias, defects in insulin-producing pancreatic cells contributing to type 1 diabetes, and protein misregulation implicated in neurodegenerative disorders. Such studies could unlock novel therapeutic targets and interventions.
The conceptual and technical foundation of SCOPE builds on prior work, especially the pioneering incorporation of the photo-reactive amino acid AbK by Dr. Peter Schultz’s laboratory. This innovative linkage chemistry has been harnessed and refined to create a tool that is both highly specific and adaptable, setting a new standard for molecular biology methodologies aimed at decoding the genome’s regulatory landscape.
Dr. Shuibing Chen, co-senior author and director of the Center for Genomic Health at Weill Cornell Medicine, emphasizes the tool’s potential to serve as a general, broadly applicable research instrument. Its design enables facile customization for various genetic targets and cell types, making it an invaluable asset for laboratories worldwide striving to unravel gene regulation complexities and their implications in health and disease.
In summary, SCOPE represents a remarkable advance in molecular biology technology. Its precision targeting, combined with the unique photo-crosslinking amino acid, enables researchers to map protein-DNA interactions with extraordinary detail and minimal background interference. This capability opens the door to transformative insights into gene regulation mechanisms that underpin cell identity, development, and disease pathogenesis. The scientific community eagerly anticipates the impact that SCOPE will have across myriad research arenas.
Subject of Research: Molecular tool for capturing DNA-binding proteins regulating gene expression
Article Title: New Tool Identifies Proteins That Control Gene Activity
News Publication Date: 29-Sep-2025
Image Credits: Dr. Jiajun Zhu
Keywords: Protein activity, Protein functions, Cell biology
