Abstract
Biomolecular condensates regulate transcription by dynamically compartmentalizing the transcription machinery. Classic models of transcription regulation focus on the recruitment and regulation of RNA polymerase II by the formation of complexes at the 1–10 nm length scale, which are driven by structured and stoichiometric interactions. These complexes are further organized into condensates at the 100–1,000 nm length scale, which are driven by dynamic multivalent interactions often involving domain–ligand pairs or intrinsically disordered regions. Regulation through condensate-mediated organization does not supersede the processes occurring at the 1–10 nm scale, but it provides regulatory mechanisms for promoting or preventing these processes in the crowded nuclear environment. Regulation of transcription by transcriptional condensates is involved in cell state transitions during animal and plant development, cell signalling and cellular responses to the environment. These condensate-mediated processes are dysregulated in developmental disorders, cancer and neurodegeneration. In this Review, we discuss the principles underlying the regulation of transcriptional condensates, their roles in physiology and their dysregulation in human diseases.
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Acknowledgements
The authors thank J. Henninger, S. Bannani, B. Li, Y. Li, Y. Lin and members of the Sabari and Li laboratories for the helpful comments and discussion. This work was supported by the National Natural Science Foundation of China grant 32125010 (P.L.), the Postdoctoral Program of Tsinghua University–Peking University Joint Center for Life Sciences, Shuimu Tsinghua Scholar Program, and Advanced Innovation Fellow programme (G.P.), Cancer Prevention and Research Institute of Texas grant RR190090 (B.R.S.), the National Institutes of Health grant GM147583 (B.R.S.) and the Robert A. Welch Foundation grants I-2163-20230405 and V-I-0004-20230731 (B.R.S.).
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Glossary
- Critical thresholds
-
Specific concentrations or condition points at which a sudden transition occurs, such as phase separation.
- DNA regulatory elements
-
DNA sequences located either proximal or distal to a gene that regulate its expression by interacting with transcription factors. Prominent examples are promoters and enhancers.
- Domain–ligand pairs
-
Interacting modules between a protein domain and its corresponding ligand.
- Histone locus body
-
A nuclear condensate associated with the active transcription of replication-dependent histone genes, which facilitates the coordination of histone mRNA transcription, processing and export during early S phase.
- Lower critical solution temperature behaviour
-
The phenomenon whereby a protein remains soluble in a solvent below a specific temperature, but above this temperature, it undergoes phase separation into condensates owing to the disruption of stabilizing interactions by increased thermal motion.
- Mediator coactivator complex
-
A multiprotein complex that acts as a bridge between transcription factors and RNA polymerase II to regulate gene activation.
- Multivalency
-
The property of a molecule or a complex that has multiple binding sites that can interact with multiple binding surfaces of another molecule or complex.
- Patterned charge blocks
-
Sequences within proteins wherein charged amino acids are organized in clusters.
- Phase separation
-
A physicochemical process through which molecules demix from the bulk environment to form dense, droplet-like structures.
- Poly-glutamine
-
A sequence motif in proteins consisting of multiple Gln residues. Some poly-glutamine tracts enhance the formation of pathological condensates or aggregates by promoting strong hydrogen bonding and intermolecular interactions often associated with neurodegenerative diseases.
- Re-entrant phase transition
-
A situation in a multi-component system in which increasing the concentration of a component initially favours the formation of condensates, but further increases lead to the disruption of the condensates.
- Skotomorphogenesis
-
The developmental process in plants that occurs in darkness, characterized by elongated stems, closed cotyledons and lack of chlorophyll synthesis.
- Transcription bursting
-
The phenomenon whereby transcription occurs in rapid, transient bursts rather than at a constant rate.
- Transcriptional condensates
-
Biomolecular condensates that concentrate components of the transcription machinery and related factors.
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Pei, G., Lyons, H., Li, P. et al. Transcription regulation by biomolecular condensates. Nat Rev Mol Cell Biol 26, 213–236 (2025). https://doi.org/10.1038/s41580-024-00789-x
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DOI: https://doi.org/10.1038/s41580-024-00789-x
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