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The Mediator complex as a master regulator of transcription by RNA polymerase II

The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo p...

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Autores principales: Richter, William F., Nayak, Shraddha, Iwasa, Janet, Taatjes, Dylan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207880/
https://www.ncbi.nlm.nih.gov/pubmed/35725906
http://dx.doi.org/10.1038/s41580-022-00498-3
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author Richter, William F.
Nayak, Shraddha
Iwasa, Janet
Taatjes, Dylan J.
author_facet Richter, William F.
Nayak, Shraddha
Iwasa, Janet
Taatjes, Dylan J.
author_sort Richter, William F.
collection PubMed
description The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo phase separation and to interact with a myriad of regulatory factors. In this Review, we discuss Mediator structure and function, with emphasis on recent cryogenic electron microscopy data of the 4.0-MDa transcription preinitiation complex. We further discuss how Mediator and sequence-specific DNA-binding transcription factors enable enhancer-dependent regulation of Pol II function at distal gene promoters, through the formation of molecular condensates (or transcription hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also discussed, in the context of transcription bursting. We propose a working model for Mediator function that combines experimental results and theoretical considerations related to enhancer–promoter interactions, which reconciles contradictory data regarding whether enhancer–promoter communication is direct or indirect. We conclude with a discussion of Mediator’s potential as a therapeutic target and of future research directions.
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spelling pubmed-92078802022-06-21 The Mediator complex as a master regulator of transcription by RNA polymerase II Richter, William F. Nayak, Shraddha Iwasa, Janet Taatjes, Dylan J. Nat Rev Mol Cell Biol Review Article The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo phase separation and to interact with a myriad of regulatory factors. In this Review, we discuss Mediator structure and function, with emphasis on recent cryogenic electron microscopy data of the 4.0-MDa transcription preinitiation complex. We further discuss how Mediator and sequence-specific DNA-binding transcription factors enable enhancer-dependent regulation of Pol II function at distal gene promoters, through the formation of molecular condensates (or transcription hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also discussed, in the context of transcription bursting. We propose a working model for Mediator function that combines experimental results and theoretical considerations related to enhancer–promoter interactions, which reconciles contradictory data regarding whether enhancer–promoter communication is direct or indirect. We conclude with a discussion of Mediator’s potential as a therapeutic target and of future research directions. Nature Publishing Group UK 2022-06-20 2022 /pmc/articles/PMC9207880/ /pubmed/35725906 http://dx.doi.org/10.1038/s41580-022-00498-3 Text en © Springer Nature Limited 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Review Article
Richter, William F.
Nayak, Shraddha
Iwasa, Janet
Taatjes, Dylan J.
The Mediator complex as a master regulator of transcription by RNA polymerase II
title The Mediator complex as a master regulator of transcription by RNA polymerase II
title_full The Mediator complex as a master regulator of transcription by RNA polymerase II
title_fullStr The Mediator complex as a master regulator of transcription by RNA polymerase II
title_full_unstemmed The Mediator complex as a master regulator of transcription by RNA polymerase II
title_short The Mediator complex as a master regulator of transcription by RNA polymerase II
title_sort mediator complex as a master regulator of transcription by rna polymerase ii
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207880/
https://www.ncbi.nlm.nih.gov/pubmed/35725906
http://dx.doi.org/10.1038/s41580-022-00498-3
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