How are extra-long genes read? A novel mechanism in which RNA-scaffolded nuclear condensates gather diverse factors to coordinate gene expression

Neurons express many extra-long genes exceeding 100 kb, but how they are accurately read remains unclear. We found that the RNA-binding protein SFPQ uses long RNAs as scaffolds to form meshwork-like nuclear condensates—membraneless assemblies of molecules. These condensates gather factors needed to read genes and process RNA, allowing them to work together. When this system is disrupted, extra-long gene expression decreases, with potential implications for neurological disorders.

Neurons in humans and other mammals express many exceptionally long genes, ranging from more than 100 kb to over 2 Mb, that are important for forming synapses and neural circuits. In general, genetic information is read from DNA into RNA. This process is called transcription. The longer a gene is, the more time it takes to read from beginning to end. In addition, gene expression must be regulated at several steps. Neurons are therefore thought to require special mechanisms to read long genes accurately and stably, but the details of these mechanisms have remained unclear.

In this study, we focused on SFPQ, a protein that binds RNA. Using super-resolution microscopy and other approaches, we found that SFPQ uses long RNAs as scaffolds to form meshwork-like structures called condensates inside the cell nucleus. Condensates are membraneless structures formed when particular molecules gather together inside cells.

We further found that these condensates bring together many molecules involved in transcription—the reading of DNA into RNA—splicing, which joins the appropriate parts of newly made RNA, and regulation of chromatin, the structure that packages DNA. When SFPQ condensates could not form, extra-long genes were not read properly to the end, RNA splicing was impaired, and gene expression decreased.

These results suggest that SFPQ condensates act as a shared ‘workspace’ that brings together several processes needed for exceptionally long genes to function properly. Our study provides insight into the physical basis of the previously proposed ‘transcriptional elongation condensate’ and offers a new way to understand gene regulation through the spatial organization of the nucleus. SFPQ and related proteins have also been linked to autism spectrum disorder (ASD) and amyotrophic lateral sclerosis (ALS). In the future, studying abnormal expression of extra-long genes may help us better understand the mechanisms of neurodevelopmental and neurodegenerative disorders.

Dev. Biol. & Funct. Genomics
https://www.m.ehime-u.ac.jp/school/anatomy1/

Reference URL: https://doi.org/10.1016/j.chembiol.2026.06.004

Bibliographic Information

Title:RNA-Dependent SFPQ Condensates Coordinate Multidimensional Regulation of Extra-Long Neuronal Genes
Authors:Motoyasu Hosokawa, Ryosuke Kawakami, Koshi Imami, Ryo Kurosawa, Takuya Yoshizawa, Yasushi Ishihama, Takeshi Imamura, Masatoshi Hagiwara, Akihide Takeuchi
Journal:Cell Chemical Biology, 2026
DOI:10.1016/j.chembiol.2026.06.004

Fundings

• Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP22H04926 (ABiS), JP15H05721, JP19K06907, JP21H05042, JP22H02797, JP25K02436, JP23K16771, JP20K17509
• Japan Agency for Medical Research and Development (AMED) Grant Number JP23ek0109497
• Takeda Science Foundation
• The Naito Foundation

Media

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  Meshwork-like condensates formed by the RNA-binding protein SFPQ and their function

  Super-resolution image of meshwork-like condensates formed by SFPQ using RNA as a scaffold in neuronal nuclei (left; green, SFPQ; red, FUS), together with a schematic showing how these structures support extra-long gene expression in neurons and how their disruption may contribute to neurological disorders (right).

  credit : Akihide Takeuchi
  Usage Restriction : Please get copyright permission

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  Gene-regulatory factors gathered within SFPQ condensates

  Proximity-dependent labeling revealed that SFPQ condensates bring together diverse molecules involved in reading genes and processing RNA.

  credit : Akihide Takeuchi
  Usage Restriction : Please get copyright permission

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  How SFPQ condensates support extra-long genes in neurons

  Conceptual illustration showing how SFPQ condensates support extra-long gene expression at multiple stages in neurons, and how disruption of this mechanism may contribute to neurological disorders.

  credit : Akihide Takeuchi, Cell Chemical Biology (2026), CC BY 4.0
  Usage Restriction : Please get copyright permission