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Transcription regulation by the Mediator complex

Key Points

  • Recent structural advances based on improvements in electron microscopy methodology have enabled the generation of high-resolution structural models of the mediator of RNA polymerase II transcription (Mediator) complex and of the preinitiation complex (PIC) in the presence of Mediator.

  • The module composition of Mediator changes between its recruitment to upstream regulatory regions (enhancers or upstream activating sequences where Mediator is bound to transcription factors) and its action on core promoters together with PIC components.

  • The functional interplay between Mediator and general transcription factors in PIC assembly is closely related to chromatin architecture at promoter regions.

  • Direct contact between Mediator and the nuclear pore-associated transcription-coupled export (TREX2) complex suggests that Mediator functions in gene positioning in the nuclear space.

  • Mediator has been shown to function in the establishment of transcriptional memory, which also involves Mediator interactions with the nuclear pore.

  • Potential therapeutic targeting and modulation of Mediator activity in cancers and in fungal infectious diseases emphasizes the importance of studies of Mediator mechanisms for improving human health.

Abstract

Alterations in the regulation of gene expression are frequently associated with developmental diseases or cancer. Transcription activation is a key phenomenon in the regulation of gene expression. In all eukaryotes, mediator of RNA polymerase II transcription (Mediator), a large complex with modular organization, is generally required for transcription by RNA polymerase II, and it regulates various steps of this process. The main function of Mediator is to transduce signals from the transcription activators bound to enhancer regions to the transcription machinery, which is assembled at promoters as the preinitiation complex (PIC) to control transcription initiation. Recent functional studies of Mediator with the use of structural biology approaches and functional genomics have revealed new insights into Mediator activity and its regulation during transcription initiation, including how Mediator is recruited to transcription regulatory regions and how it interacts and cooperates with PIC components to assist in PIC assembly. Novel roles of Mediator in the control of gene expression have also been revealed by showing its connection to the nuclear pore and linking Mediator to the regulation of gene positioning in the nuclear space. Clear links between Mediator subunits and disease have also encouraged studies to explore targeting of this complex as a potential therapeutic approach in cancer and fungal infections.

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Figure 1: Transcription activation by RNA polymerase II.
Figure 2: Subunit composition of the Mediator complex.
Figure 3: Mediator recruitment and transient association with the core promoter.
Figure 4: Mediator interplay with the preinitiation complex and with promoter architecture.
Figure 5: Mediator links to the nuclear pore complex.

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Acknowledgements

The author apologizes to the colleagues whose work could not be cited owing to space limitations. The work of J.S. is funded by the Agence Nationale de la Recherche (ANR-14-CE10-0012-01) and the Fondation ARC (grant nos SL220130607079 and PGA1 RF20170205342).

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Supplementary information S1 (table)

Recent structural models of Mediator complex (PDF 131 kb)

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Glossary

Specific transcription factors

Also known as sequence-specific DNA-binding factors (which serve as activators or repressors) that bind to specific DNA sequences in regulatory regions and are essential for regulated transcription.

Co-regulators

Multisubunit protein complexes (which serve as co-activators or co-repressors) that interact with transcription factors and participate in transcription regulation. This group includes complexes that directly influence the basal assembly of transcriptional machinery as well as chromatin modifiers or remodellers that act on a chromatin structure.

General transcription factors

(GTFs). Proteins or protein complexes that are essential for promoter recognition by RNA polymerase II (Pol II), its function and recruitment. This class of proteins were identified as essential components for basal transcription from a specific promoter from in vitro Pol II transcription assays.

Preinitiation complex

(PIC). A large protein complex that assembles on core promoters to position the RNA polymerase. The main components of the PIC of RNA polymerase II (Pol II) are six general transcription factors, Pol II and Mediator.

Core promoters

Minimal DNA sequences close to the transcription start site (TSS) that are sufficient to direct accurate transcription initiation. TATA-elements represent one of the core-promoter elements.

TATA-elements

Consensus sequences (such as TATA-boxes) or sequences presenting some mismatches from the consensus (such as TATA-like elements) in promoters that are bound by TATA-box binding protein.

Pol II carboxy-terminal domain

(CTD) A domain of the largest RNA polymerase II (Pol II) subunit that is important for various steps of the transcription cycle and RNA processing and contains multiple repeats of the heptapeptide sequence YSPTSPS, which are subject to phosphorylation (at Ser2, Ser5 and Ser7) and other post-translational modifications.

Activating RNAs

Long non-coding RNAs with enhancer-like function that interact with Mediator and activate their neighbouring genes.

Enhancer RNAs

Non-coding RNAs that are transcribed from enhancers and contribute to gene looping between enhancers and promoters and thus to gene transcription regulation.

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Soutourina, J. Transcription regulation by the Mediator complex. Nat Rev Mol Cell Biol 19, 262–274 (2018). https://doi.org/10.1038/nrm.2017.115

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