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Enhancer–promoter entanglement explains their transcriptional interdependence

Enhancers not only activate target promoters to stimulate messenger RNA (mRNA) synthesis, but they themselves also undergo transcription to produce enhancer RNAs (eRNAs), the significance of which is not well understood. Transcription at the participating enhancer–promoter pair appears coordinated,...

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Detalles Bibliográficos
Autores principales: Panigrahi, Anil K., Lonard, David M., O’Malley, Bert W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942820/
https://www.ncbi.nlm.nih.gov/pubmed/36656865
http://dx.doi.org/10.1073/pnas.2216436120
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author Panigrahi, Anil K.
Lonard, David M.
O’Malley, Bert W.
author_facet Panigrahi, Anil K.
Lonard, David M.
O’Malley, Bert W.
author_sort Panigrahi, Anil K.
collection PubMed
description Enhancers not only activate target promoters to stimulate messenger RNA (mRNA) synthesis, but they themselves also undergo transcription to produce enhancer RNAs (eRNAs), the significance of which is not well understood. Transcription at the participating enhancer–promoter pair appears coordinated, but it is unclear why and how. Here, we employ cell-free transcription assays using constructs derived from the human GREB1 locus to demonstrate that transcription at an enhancer and its target promoter is interdependent. This interdependence is observable under conditions where direct enhancer–promoter contact (EPC) takes place. We demonstrate that transcription activation at a participating enhancer–promoter pair is dependent on i) the mutual availability of the enhancer and promoter, ii) the state of transcription at both the enhancer and promoter, iii) local abundance of both eRNA and mRNA, and iv) direct EPC. Our results suggest transcriptional interdependence between the enhancer and the promoter as the basis of their transcriptional concurrence and coordination throughout the genome. We propose a model where transcriptional concurrence, coordination and interdependence are possible if the participating enhancer and promoter are entangled in the form of EPC, reside in a proteinaceous bubble, and utilize shared transcriptional resources and regulatory inputs.
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spelling pubmed-99428202023-02-22 Enhancer–promoter entanglement explains their transcriptional interdependence Panigrahi, Anil K. Lonard, David M. O’Malley, Bert W. Proc Natl Acad Sci U S A Biological Sciences Enhancers not only activate target promoters to stimulate messenger RNA (mRNA) synthesis, but they themselves also undergo transcription to produce enhancer RNAs (eRNAs), the significance of which is not well understood. Transcription at the participating enhancer–promoter pair appears coordinated, but it is unclear why and how. Here, we employ cell-free transcription assays using constructs derived from the human GREB1 locus to demonstrate that transcription at an enhancer and its target promoter is interdependent. This interdependence is observable under conditions where direct enhancer–promoter contact (EPC) takes place. We demonstrate that transcription activation at a participating enhancer–promoter pair is dependent on i) the mutual availability of the enhancer and promoter, ii) the state of transcription at both the enhancer and promoter, iii) local abundance of both eRNA and mRNA, and iv) direct EPC. Our results suggest transcriptional interdependence between the enhancer and the promoter as the basis of their transcriptional concurrence and coordination throughout the genome. We propose a model where transcriptional concurrence, coordination and interdependence are possible if the participating enhancer and promoter are entangled in the form of EPC, reside in a proteinaceous bubble, and utilize shared transcriptional resources and regulatory inputs. National Academy of Sciences 2023-01-19 2023-01-24 /pmc/articles/PMC9942820/ /pubmed/36656865 http://dx.doi.org/10.1073/pnas.2216436120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Panigrahi, Anil K.
Lonard, David M.
O’Malley, Bert W.
Enhancer–promoter entanglement explains their transcriptional interdependence
title Enhancer–promoter entanglement explains their transcriptional interdependence
title_full Enhancer–promoter entanglement explains their transcriptional interdependence
title_fullStr Enhancer–promoter entanglement explains their transcriptional interdependence
title_full_unstemmed Enhancer–promoter entanglement explains their transcriptional interdependence
title_short Enhancer–promoter entanglement explains their transcriptional interdependence
title_sort enhancer–promoter entanglement explains their transcriptional interdependence
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942820/
https://www.ncbi.nlm.nih.gov/pubmed/36656865
http://dx.doi.org/10.1073/pnas.2216436120
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