Genes are copied to make RNA transcripts, then the copies, or transcripts, are translated into proteins. The transcripts, known as pre-messenger-RNA (pre-mRNA) are processed in the cellular nucleus to generate bona fide mRNAs that are then translated by ribosomes. This processing, known as splicing, happens in a cellular region known as nuclear speckles. Errors in splicing, which can happen as a function of aging, during cellular stress, or during aberrant cellular responses, directly contribute to the onset and progress of various cancers and are associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS).
Speckles are thought to be biomolecular condensates, where DNA, RNA and proteins are organized into distinct molecular communities that form via phase separation. Rohit V. Pappu, PhD, the Gene K. Beare Distinguished Professor of Biomedical Engineering in the McKelvey School of Engineering at Washington University in St. Louis, and Min Kyung Shinn, a former postdoctoral researcher in his lab, investigated some of the physical features of nuclear speckles that were inconsistent with the type of uniform droplets one expected to see if they formed via liquid-liquid phase separation.
Shinn and Pappu set out to reconstitute the phase transitions of various RNA-binding proteins that belong to nuclear speckles, after discussing the issue with K.V. Prasanth, professor of cell & developmental biology at University of Illinois Urbana-Champaign and an expert in nuclear speckles. Results of their research were published in Cell Dec. 19, 2025.
Right away, their microscopy images revealed that the speckle-associated proteins were distinct in the types of structures they formed.
“We realized that the RNA binding proteins, which feature distinct combinations of folded RNA recognition motifs (RRMs) and distinct types of intrinsically disordered regions (IDRs), fit the description of being unconventional block copolymers,” Pappu said. “These types of molecules, which have regions that favor versus disfavor interactions with the solvent, are known to form micelles or microphases. Within such nanometer-sized block copolymeric molecules and form assemblies that are on the order of tens of nanometers in size, encompassing tens to hundreds of molecules depending on the molecular architectures and the nature of the intermolecular and inter-block interactions.”