How Neurons Transcribe Massive Genes

Summary:

Researchers have discovered that neurons rely on meshwork-like biomolecular condensates formed by the RNA-binding protein SFPQ to transcribe and process extra-long genes spanning millions of base pairs. When these nuclear condensates fail to form, transcription stalls and splicing breaks down, shedding light on potential pathological mechanisms behind autism spectrum disorder and ALS.

Key Facts:

Specialized Nuclear Scaffolding: The RNA-binding protein SFPQ uses nascent long RNAs as structural scaffolds to form membraneless biomolecular condensates inside neuronal nuclei.
Multidimensional Workspace: These meshwork-like condensates physically concentrate diverse machineries—including transcriptional elongation factors, splicing regulators, and chromatin remodelers—ensuring ultra-long genes (over 100 kb to >2 Mb) are transcribed to completion.
Implications for Neurodevelopment and ALS: Disrupting SFPQ condensates causes premature transcription arrest and splicing errors in critical synaptic genes, many of which overlap with risk genes for autism spectrum disorder (ASD) and amyotrophic lateral sclerosis (ALS).

Source: Ehime University

Unraveling the Mystery of Extra-Long Neuronal Genes

Neurons in the human and mammalian central nervous system face a unique genomic hurdle: to wire neural circuits and maintain complex synaptic networks, they must actively transcribe exceptionally long genes. Spanning anywhere from several hundred thousand base pairs to upwards of two million base pairs, these giant genes take hours or even days to transcribe from start to finish.

Despite the enormous physical scale of these genes, how neurons sustain continuous transcription and simultaneously orchestrate RNA splicing without molecular chaos has remained an unresolved puzzle.

This shows neurons. — Conceptual visualization of meshwork-like biomolecular condensates forming inside a neuronal nucleus, organizing molecular complexes along RNA scaffolds to transcribe exceptionally long genes. Credit: Neuroscience News

Now, a research team led by Dr. Akihide Takeuchi at Ehime University has unmasked the nuclear architecture responsible for coordinating this feat. In a study published in Cell Chemical Biology, researchers identified specialized membraneless compartments—known as biomolecular condensates—that act as dedicated hubs to read and assemble long neuronal transcripts.

RNA-Scaffolded “Workspaces” Inside the Nucleus

Cells frequently organize their interior without physical lipid membranes via a process known as liquid-liquid phase separation. Focusing on SFPQ (splicing factor proline- and glutamine-rich), a multifunctional RNA-binding protein, the scientists utilized super-resolution microscopy alongside proximity-dependent biotin labeling (BioID) and mass spectrometry.

Their imaging revealed that SFPQ binds directly to newly synthesizing RNA strands, using them as structural scaffolding to assemble meshwork-like condensates throughout the neuronal nucleus. Rather than drifting randomly across the nucleoplasm, essential molecular machineries congregate directly within these droplet-like assemblies.

Inside these SFPQ condensates, three vital stages of gene regulation operate in tight synergy:

Chromatin remodeling: Unpacking tightly coiled DNA to allow the transcriptional machinery smooth passage.
Transcriptional elongation: Keeping RNA polymerase processive across millions of nucleotides without premature detachment.
Co-transcriptional splicing: Precision-cutting and stitching exons as the nascent RNA molecule emerges.

“These condensates act as a shared ‘workspace’ bringing together several processes required for exceptionally long genes to function properly,” the authors note.

Vulnerabilities in Brain Disorders: ASD and ALS

To understand what happens when this workspace breaks down, the researchers performed functional disruption assays. Without stable SFPQ condensates, the transcription of extra-long genes halted prematurely, RNA splicing faltered, and overall gene expression plummeted.

Crucially, the proteins enriched within SFPQ condensates heavily overlap with genes implicated in neurodevelopmental and neurodegenerative diseases. Both SFPQ and its partner proteins (such as FUS) have longstanding genetic links to autism spectrum disorder (ASD) and amyotrophic lateral sclerosis (ALS).

Because synaptic connectivity relies so heavily on giant structural and signaling proteins, neurons are acutely vulnerable when this nuclear assembly line collapses. The authors suggest that studying the structural failure of SFPQ condensates provides a new window into “long-gene transcriptopathies,” offering potential therapeutic targets aimed at stabilizing nuclear architecture in neurological disorders.

Editorial Notes:

This article was edited by a Neuroscience News editor.
Journal paper reviewed in full.
Additional context added by our staff.

About this Neurodevelopment Research:

Media Contact: Takuya Imaoka
Source: Ehime University
Image Credit: Image generated for Neuroscience News
Original Research is Open Access: Cell Chemical Biology (September 2, 2026). “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

Abstract

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

Regulation of extra-long genes (>100 kbp) is essential for neuronal development and function; yet, how multiple regulatory processes are coordinated across such long genomic regions remains poorly understood. Here, we identify transcriptional elongation condensates formed by the RNA-binding protein SFPQ via liquid-liquid phase separation (LLPS), which assemble multi-layered regulatory complexes to coordinate gene expression of extra-long neuronal genes.

Using super-resolution imaging, biochemical reconstitution, and functional analyses, we show that SFPQ forms meshwork-like condensates in the presence of long pre-mRNAs. These condensates exhibit LLPS-like properties and depend on both RNA-binding and protein-protein interaction domains of SFPQ. Disruption of meshwork condensate organization impairs splicing and selectively reduces expression of extra-long genes, revealing a functional relationship between condensate architecture and gene regulation.

Proximity labeling combined with mass spectrometry further reveal that SFPQ condensates associate with diverse regulatory factors involved in RNA splicing, transcriptional elongation, and chromatin regulation, indicating that SFPQ meshwork condensates function as transcriptional elongation condensates that integrate multiple layers of gene regulation within the nucleoplasm. Consistently, transcriptomic analyses show preferential dysregulation of extra-long genes enriched for neuronal development and synaptic function.

SFPQ condensates are largely distinct from canonical nuclear condensates such as paraspeckles and nuclear speckles, supporting the existence of a unique RNA-dependent regulatory architecture. Network analysis further demonstrates enrichment of autism spectrum disorder (ASD)-associated genes within SFPQ-associated regulatory complexes, suggesting a mechanistic link between condensate organization and neurodevelopmental disorders.

Many RNA-binding proteins, including FUS and TDP-43, form LLPS-based condensates and are implicated in neurological diseases; yet, their physiological roles remain incompletely understood. Our findings provide a conceptual and experimental framework for RNA-dependent gene regulation and offer insight into how disruption of nuclear condensate architecture contributes to neurological disease.