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Review
. 2022 Jan 15;434(1):167216.
doi: 10.1016/j.jmb.2021.167216. Epub 2021 Aug 30.

Merging Established Mechanisms with New Insights: Condensates, Hubs, and the Regulation of RNA Polymerase II Transcription

Megan Palacio  1 , Dylan J Taatjes  2
Affiliations
Review

Merging Established Mechanisms with New Insights: Condensates, Hubs, and the Regulation of RNA Polymerase II Transcription

Megan Palacio et al. J Mol Biol. .

Abstract

The regulation of RNA polymerase II (pol II) transcription requires a complex and context-specific array of proteins and protein complexes, as well as nucleic acids and metabolites. Every major physiological process requires coordinated transcription of specific sets of genes at the appropriate time, and a breakdown in this regulation is a hallmark of human disease. A proliferation of recent studies has revealed that many general transcription components, including sequence-specific, DNA-binding transcription factors, Mediator, and pol II itself, are capable of liquid-liquid phase separation, to form condensates that partition these factors away from the bulk aqueous phase. These findings hold great promise for next-level understanding of pol II transcription; however, many mechanistic aspects align with more conventional models, and whether phase separation per se regulates pol II activity in cells remains controversial. In this review, we describe the conventional and condensate-dependent models, and why their similarities and differences are important. We also compare and contrast these models in the context of genome organization and pol II transcription (initiation, elongation, and termination), and highlight the central role of RNA in these processes. Finally, we discuss mutations that disrupt normal partitioning of transcription factors, and how this may contribute to disease.

Keywords: RNA polymerase II; condensates; liquid-liquid phase separation; mediator; transcription.

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Conflict of interest statement

Competing interest statement D.J.T. is a member of the scientific advisory board at Dewpoint Therapeutics.

Figures

Figure 1:
Figure 1:. Molecular interactions that can drive phase separation
A) Two different proteins (orange) with structured and intrinsically disordered regions (IDR) are shown schematically, with different chemical properties due to their different amino acid sequences. Structural details of potential transient, low-affinity interactions between the IDRs are shown at left, representing simplified schematics for pi-cation, pi-pi, or ionic interactions. B) A simplified schematic of a phase separated condensate is shown at right, with disordered proteins and RNA partitioned within the condensate. At left are representative ionic interactions that could transiently occur between a protein IDR and the RNA phosphate backbone. Note that the RNA bases (A, U, G, C) are hydrophobic and can also participate in intermolecular interactions through hydrogen bonding (H-bonding).
Figure 2:
Figure 2:. Speculative models for condensate-dependent regulation of pol II transcription
A) At some genes, low levels of eRNAs combined with high local concentration of TFs, Mediator, pol II, and other factors may cause condensate formation. The condensate may favor high-level activation (vs. bulk aqueous phase) that could be important during developmental or stress responses or for robust expression of lineage-specific genes. After pol II initiation and promoter escape (left), a second pol II could then engage the PIC scaffold to re-initiate transcription (right). Re-initiation would be enhanced by high local pol II concentration, driven by pol II CTD-dependent phase separation. B) After initiation, promoter escape, and promoter-proximal pause release, pol II separates from the PIC and enters an elongation state. During elongation, pol II associates with a different set of protein complexes (e.g. DSIF) and the pol II CTD is highly phosphorylated. This distinct environment may enable compartmentalization of elongation and initiation condensates. Such compartmentalization could promote more efficient elongation and RNA processing, perhaps through associated nuclear speckles.
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