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In a new study in Cell, the group of Tuğçe Aktaş (MPIMG) in collaboration with scientists from the LJI (USA) and Kyoto University (Japan), shows that condensates in the cell nucleus known as nuclear speckles help process RNA transcribed from the most gene dense regions of the genome. These findings provide an answer to the long-standing question about the function of these condensates.
The problem with nuclear speckles
Nuclear speckles have long puzzled scientists. With the advent of light microscopy, researchers first observed granular structures within cell nuclei. Yet these speckles were not formally recognized as distinct nuclear entities until the mid-20th century. Advanced molecular biology methods finally revealed their composition, but this insight only raised even more questions.
“Broadly speaking, the field was considering two different ideas,” says group leader Tuğçe Aktaş. “Some scientists thought they were a gene-expression regulatory hub because they contain many transcription- and splicing-related proteins. Others believed that speckles simply store these molecules until they are needed and are not functional bodies.”
But how could their function be determined? In molecular biology, a basic approach is to delete a structure or protein of interest and observe the resulting effects on cells and biological processes. However, this approach was long hindered by the complexity of nuclear speckles. “They contain hundreds of proteins, and it was unclear which ones formed the core of these condensates” explains Michal Malszycki, one of the study’s first authors.
The functions of speckles
This changed in 2020, when the Aktaş lab identified the two proteins that form the scaffold of nuclear speckles: SON and SRRM2. In their new study, the researchers targeted these proteins with degraders and were finally able to disrupt the structures. “By dismantling speckles, we found that they have a clear function and are not merely storage spaces,” says Aktaş.
Specifically, the team linked speckle function to regions of DNA known as GC-rich isochores – large segments of DNA that are highly enriched in guanine and cytosine bases. “These GC-rich regions are dense with genes, and the messenger RNA produced from them is difficult to splice by default,” explains Lisa Martina, another first author. “We can now show that speckles are needed to properly process this tightly packed gene architecture.” Another function is to restrict random chromatin movements, as it was revealed by the 3D chromatin conformation capture techniques that Aktaş lab performed together with the group of Ferhat Ay at LJI in San Diego.
The scientists also performed experiments in cell lines of other species, some of which were only available thanks to their collaborator Cantas Alev at ASHBi in Kyoto. The authors discovered that speckles seem to have evolved in amniotes, such as mammals and birds together with the gene architecture that is difficult to splice, but are absent in fish or invertebrates.
“We found that speckles and the GC-rich isochores have coevolved. Why isochores exist, or what advantage such gene architecture provides, remains controversial. But this finding raises important questions about the evolution of speckles and their roles in other species, which we will now pursue further,” says İbrahim Ilık, a postdoc in the lab and a co-author of the paper.
Speckles in diseases
The core proteins of nuclear speckles are frequently mutated in rare disorders and there are some recent studies that report changes in the composition and morphology of speckles in cancer. A deeper understanding of the biophysical properties of these speckles could also provide important insights into disease mechanisms.
More broadly, biomolecular condensates, such as nuclear speckles, are increasingly implicated in key cellular functions and in many diseases. “There were all these ideas about what nuclear speckles might be doing, and it is very exciting that we can clearly link them to the processing of the GC-rich isochore-derived RNA. To the best of my knowledge, no one has ever described a nuclear condensate that specifically affects such large domains of the genome,” concludes Aktaş.
Malszycki M. et.al. Nuclear Speckles enable processing of RNA from GC-rich Isochores.
Cell 2026. https://doi.org/10.1016/j.cell.2026.01.011
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