How Neurons Transcribe Long Genes

Summary:

Researchers have identified a critical nuclear architecture that neurons use to transcribe and process exceptionally long genes. The RNA-binding protein SFPQ assembles meshwork-like, membraneless condensates on nascent long RNAs, concentrating the molecular machinery needed for continuous transcription and co-transcriptional splicing. Failure of these condensates causes transcriptional arrest and splicing defects in ultra-long neuronal genes, providing insight into mechanisms that may underlie autism spectrum disorder (ASD) and amyotrophic lateral sclerosis (ALS).

Key Facts:

1. Specialized nuclear scaffolding: SFPQ uses newly synthesized long RNAs as structural scaffolds to form membraneless biomolecular condensates within neuronal nuclei.
2. Multidimensional workspace: These meshwork condensates recruit and concentrate transcriptional elongation factors, splicing regulators, and chromatin remodelers so ultra-long genes (from >100 kb up to >2 Mb) can be read and processed to completion.
3. Relevance to neurodevelopment and neurodegeneration: Disruption of SFPQ condensates leads to premature transcription termination and splicing errors in key synaptic genes, many of which overlap with ASD and ALS risk genes.

Source: Ehime University

Unraveling the Mystery of Extra-Long Neuronal Genes

Neurons in the mammalian central nervous system face a distinct challenge: building and maintaining complex synapses requires the expression of exceptionally long genes. These genes, which can span hundreds of kilobases to more than two megabases, take many hours or even days to transcribe.

Until now, it has been unclear how neurons sustain uninterrupted transcription across such vast genomic distances while coordinating accurate RNA splicing and chromatin remodeling. A team led by Dr. Akihide Takeuchi at Ehime University has described a nuclear organization that resolves this challenge: RNA-dependent SFPQ condensates that act as integrated hubs for long-gene expression.

RNA-Scaffolded “Workspaces” Inside the Nucleus

Many cellular compartments form without membranes through liquid-liquid phase separation. Examining SFPQ (splicing factor proline- and glutamine-rich), the researchers combined super-resolution microscopy, proximity-dependent biotin labeling (BioID), and mass spectrometry to map its nuclear behavior and interactions.

They found SFPQ binds directly to nascent long pre-mRNAs, using these RNA molecules as structural scaffolds to assemble a meshwork of condensates distributed across the nucleoplasm. Rather than acting as isolated droplets, these meshworks create interconnected workspaces where multiple gene-regulatory processes are co-localized.

Within SFPQ condensates, three central activities are coordinated:

• Chromatin remodeling: Making the DNA template accessible so polymerases can progress.
• Transcriptional elongation: Sustaining RNA polymerase processivity over extremely long genomic regions to prevent premature termination.
• Co-transcriptional splicing: Processing introns and exons while the nascent transcript is being synthesized.

By concentrating regulators of these processes, SFPQ condensates act as shared nuclear workspaces that help ensure fidelity and continuity of long-gene expression.

Vulnerabilities in Brain Disorders: ASD and ALS

Functional disruption experiments showed that when SFPQ condensate architecture is compromised, transcription of extra-long genes stalls, splicing fidelity declines, and overall expression of those genes drops sharply. Many affected genes encode synaptic proteins crucial to neuronal connectivity and signaling.

Proteins enriched in SFPQ condensates include known neurodevelopmental and neurodegenerative risk factors. SFPQ itself and interacting partners such as FUS have established genetic links to autism spectrum disorder and amyotrophic lateral sclerosis. Because neurons rely on large structural and signaling proteins generated from ultra-long transcripts, collapse of this nuclear assembly line likely creates specific vulnerability in neural tissue.

The authors propose that disruptions in condensate formation represent a form of “long-gene transcriptopathy,” and that stabilizing these RNA-dependent architectures could be a promising therapeutic strategy for disorders that involve impaired long-gene expression.

Editorial Notes:

• This piece was edited by a Neuroscience News editor.
• The journal paper was reviewed in full and contextualized by staff.

About this Neurodevelopment Research:

• Media Contact: Takuya Imaoka
• Source: Ehime University
• Image Credit: Image generated for Neuroscience News
• Original Research (Open Access): Cell Chemical Biology (September 2, 2026). 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, and Akihide Takeuchi.
• DOI: 10.1016/j.chembiol.2026.06.004

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Abstract

RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes

Proper regulation of extra-long genes (>100 kbp) is essential for neuronal development and function, yet the coordination of multiple regulatory steps across such extended genomic regions has been unclear. This study identifies transcriptional elongation condensates formed by the RNA-binding protein SFPQ through liquid-liquid phase separation (LLPS). These condensates assemble multi-layered regulatory complexes that coordinate expression of extra-long neuronal genes.

Using super-resolution imaging, biochemical reconstitution, and functional assays, the researchers demonstrated that SFPQ forms meshwork-like condensates in the presence of long pre-mRNAs. These assemblies depend on both SFPQ’s RNA-binding activity and its protein-protein interaction domains, and they show LLPS-like properties. Disrupting the meshwork impairs splicing and selectively reduces expression of extra-long genes, linking condensate architecture to gene regulation.

Proximity labeling combined with mass spectrometry revealed that SFPQ condensates associate with diverse factors for RNA splicing, transcriptional elongation, and chromatin regulation, supporting their role as integrated elongation condensates. Transcriptomic analyses confirmed preferential dysregulation of extra-long genes enriched for neuronal development and synaptic functions when condensates were disrupted.

SFPQ condensates are largely distinct from canonical nuclear bodies such as paraspeckles and nuclear speckles, indicating a unique RNA-dependent regulatory architecture. Network analysis showed enrichment of autism spectrum disorder–associated genes within SFPQ-associated complexes, suggesting a mechanistic connection between condensate organization and neurodevelopmental disorders.

Many RNA-binding proteins implicated in neurological diseases form LLPS-based condensates; however, their physiological roles are not fully defined. These results provide a conceptual and experimental framework for RNA-dependent regulation of long genes and offer insight into how breakdown of nuclear condensate architecture can contribute to neurological disease.