Inside cells, RNAs and proteins form tiny, liquid droplets called biomolecular condensates. These droplets are essential for the organization of cellular life, yet why some RNAs aggregate more easily than others remains unclear. Disorders in the formation of condensates are linked to developmental defects, cancer and neurodegenerative diseases. Researchers at the Karlsruhe Institute of Technology (KIT) have now identified a new class of RNAs called smOOPs and gained a better understanding of how biomolecular condensates form. The findings were published in the journal Cell Genomics. (DOI: 10.1016/j.xgen.2025.101065)
Within human cells lies a dynamic interior. Biological condensates function as organizational hubs, supporting a wide range of cellular functions from gene regulation to stress responses.
These biological condensates are accumulations that arise through phase separation, a process in which molecules separate from their surroundings—much like how oil separates from water. Inside cells, this process causes RNA and proteins to form discrete membrane-less droplets.”
Professor Miha Modic, Zoological Institute at KIT
In a new study, conducted in collaboration with researchers from the National Institute of Chemistry in Slovenia and the Francis Crick Institute, Modic’s team combined experimental analyzes with deep learning to determine which RNAs tend to aggregate during the formation of condensates. Using this approach, the researchers identified a previously unknown class of RNAs acting during early development and named them smOOPs (semi-extractable and orthogonal RNAs enriched by organic phase separation).
Sticky RNAs affect cellular organization
“During early development, each cell state expresses a distinct set of condensation-prone RNAs. These RNAs ‘tune’ or span the phase-separation landscape of that cell,” Modic says. “We discovered that smOOPs are unusually ‘sticky’, highly cell-type specific, and present during early development. They resist standard RNA extraction methods and are highly bound by RNA-binding proteins.” Additionally, the researchers observed that smOOPs visibly cluster within cells and are more interconnected than expected, demonstrating that they naturally prefer to condense inside cells.
Using deep learning, the researchers found that smOOPs share distinctive features. long transcripts with lower sequence complexity, strong internal folding and characteristic protein binding patterns. It was found that the proteins encoded by these RNAs also tend to contain long, flexible segments, which also promote condensation. “This indicates an interesting interplay between RNA-based and protein-based features in phase separation,” says Modic. “The discovery of smOOPs not only expands our understanding of condensation-prone RNAs, but also shows how combining biochemical experiments with deep machine learning can reveal the hidden logic of life’s molecular networks.”
New clues to condensate formation drive further research
Investigating how cells maintain their internal organization is crucial to understanding our biology. “Both RNA and protein contribute to the formation of condensates. This coupling becomes particularly important in development. When this mechanism malfunctions, it causes disease,” explains Modic. “By identifying smOOPs and their RNA-RNA interaction network, we now have a conceptual and mechanistic framework for interpreting pathogenic condensations in disease.”
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