Novel Role for Disordered Protein in Coordinating Key Stages of Gene Expression

In a new study published in Cell Reports, researchers at the University of Freiburg detail how a disordered protein fragment connects two key stages of gene expression: transcription and RNA editing.

The protein, TAF2, is part of the general transcription factor TFIID. Within TAF2, an intrinsically disordered region (IDR) acts as a built-in localization signal, directing the protein to specific sites within the cell nucleus.

The study highlights that flexible protein regions like TAF2’s IDR not only influence the spatial organization of molecular processes but can also serve as regulators by targeting specific functions, such as localization to nuclear speckles, a mechanism potentially relevant to disease.

Led by Dr. Tanja Bhuiyan, corresponding author and postdoctoral researcher at the University of Freiburg’s Institute of Experimental and Clinical Pharmacology and Toxicology and the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies, the study reveals a previously unrecognized regulatory role for a class of protein domains common in nuclear proteins but still poorly understood.

A Flexible Signal That Guides Molecular Coordination

TAF2’s IDR directs the protein to nuclear speckles—liquid-like compartments that concentrate RNA processing components—rather than to active gene promoters, where it functions in transcription initiation. Using a combination of proteomics, genome-wide sequencing, and advanced imaging, the team showed that TAF2 can actively move between different nuclear sites, adopting distinct roles depending on its location.

We found that TAF2 does not just operate at gene promoters as part of the classical TFIID complex. Instead, this flexible region allows it to move between different nuclear compartments, enabling it to interact with RNA-processing machinery and help shape how gene messages are finalised.

Tanja Bhuiyan, Study Corresponding Author and Postdoctoral Researcher, University of Freiburg

The researchers identified three functional pools of nuclear TAF2: one concentrated in nuclear speckles, another in non-canonical complexes with the splicing factor SRRM2, and a third within canonical TFIID complexes near gene promoters. When the IDR was removed, TAF2 failed to localize to nuclear speckles and instead accumulated more at gene promoters.

Interestingly, this shift, linked to alternative splicing, a process that enables cells to produce different proteins from the same gene, did not significantly alter global gene expression. However, it did affect how certain RNA transcripts were processed.

From Structure to Impact: Linking Transcription to RNA Editing

This suggests that the spatial routing of TAF2 does not switch genes on or off in a binary way. It rather modulates how information is processed at the RNA level, a more subtle but potentially powerful form of gene regulation.

Dr. Sebastian Arnold, Study Last Author and Professor, University of Freiburg

Arnold is also a Group Leader at the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Freiburg and at the CIBSS – Centre for Integrative Biological Signalling Studies.

These findings enhance our understanding of how cells coordinate complex molecular processes in both space and time. Many regulatory pathways depend not only on linear signaling cascades but also on dynamic spatial compartmentalization and molecular flexibility. The study highlights the growing importance of IDRs.

Once thought to be structurally ambiguous, IDRs are now recognized as key elements in the formation of biomolecular condensates and in regulating functional specificity. TAF2’s IDR contains a conserved sequence rich in histidine and lysine residues, supporting the idea that phase separation–driven targeting to nuclear speckles may represent a broader principle in gene regulation.

While the study did not directly examine disease mechanisms, several alternative splicing events influenced by TAF2 involved genes linked to neurodevelopment and membrane transport. These results suggest that TAF2’s spatial dynamics may have wider biological relevance. Future research may explore how this regulatory mechanism affects cell identity, stress responses, and disease processes.