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DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell

An important characteristic of cell differentiation is its stability. Only rarely do cells or their stem cell progenitors change their differentiation pathway. If they do, it is often accompanied by a malfunction such as cancer. A mechanistic understanding of the stability of differentiated states w...

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Autores principales: Javed, Khayam, Jullien, Jerome, Agarwal, Gaurav, Lawrence, Nicola, Butler, Richard, Ioannou, Pantelis Savvas, Nazir, Farhat, Gurdon, J. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795562/
https://www.ncbi.nlm.nih.gov/pubmed/35074915
http://dx.doi.org/10.1073/pnas.2116091119
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author Javed, Khayam
Jullien, Jerome
Agarwal, Gaurav
Lawrence, Nicola
Butler, Richard
Ioannou, Pantelis Savvas
Nazir, Farhat
Gurdon, J. B.
author_facet Javed, Khayam
Jullien, Jerome
Agarwal, Gaurav
Lawrence, Nicola
Butler, Richard
Ioannou, Pantelis Savvas
Nazir, Farhat
Gurdon, J. B.
author_sort Javed, Khayam
collection PubMed
description An important characteristic of cell differentiation is its stability. Only rarely do cells or their stem cell progenitors change their differentiation pathway. If they do, it is often accompanied by a malfunction such as cancer. A mechanistic understanding of the stability of differentiated states would allow better prospects of alleviating the malfunctioning. However, such complete information is yet elusive. Earlier experiments performed in Xenopus oocytes to address this question suggest that a cell may maintain its gene expression by prolonged binding of cell type–specific transcription factors. Here, using DNA competition experiments, we show that the stability of gene expression in a nondividing cell could be caused by the local entrapment of part of the general transcription machinery in transcriptionally active regions. Strikingly, we found that transcriptionally active and silent forms of the same DNA template can stably coexist within the same nucleus. Both DNA templates are associated with the gene-specific transcription factor Ascl1, the core factor TBP2, and the polymerase II (Pol-II) ser5 C-terminal domain (CTD) phosphorylated form, while Pol-II ser2 CTD phosphorylation is restricted to the transcriptionally dominant template. We discover that the active and silent DNA forms are physically separated in the oocyte nucleus through partition into liquid–liquid phase-separated condensates. Altogether, our study proposes a mechanism of transcriptional regulation involving a spatial entrapment of general transcription machinery components to stabilize the active form of a gene in a nondividing cell.
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spelling pubmed-87955622022-02-03 DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell Javed, Khayam Jullien, Jerome Agarwal, Gaurav Lawrence, Nicola Butler, Richard Ioannou, Pantelis Savvas Nazir, Farhat Gurdon, J. B. Proc Natl Acad Sci U S A Biological Sciences An important characteristic of cell differentiation is its stability. Only rarely do cells or their stem cell progenitors change their differentiation pathway. If they do, it is often accompanied by a malfunction such as cancer. A mechanistic understanding of the stability of differentiated states would allow better prospects of alleviating the malfunctioning. However, such complete information is yet elusive. Earlier experiments performed in Xenopus oocytes to address this question suggest that a cell may maintain its gene expression by prolonged binding of cell type–specific transcription factors. Here, using DNA competition experiments, we show that the stability of gene expression in a nondividing cell could be caused by the local entrapment of part of the general transcription machinery in transcriptionally active regions. Strikingly, we found that transcriptionally active and silent forms of the same DNA template can stably coexist within the same nucleus. Both DNA templates are associated with the gene-specific transcription factor Ascl1, the core factor TBP2, and the polymerase II (Pol-II) ser5 C-terminal domain (CTD) phosphorylated form, while Pol-II ser2 CTD phosphorylation is restricted to the transcriptionally dominant template. We discover that the active and silent DNA forms are physically separated in the oocyte nucleus through partition into liquid–liquid phase-separated condensates. Altogether, our study proposes a mechanism of transcriptional regulation involving a spatial entrapment of general transcription machinery components to stabilize the active form of a gene in a nondividing cell. National Academy of Sciences 2022-01-24 2022-01-25 /pmc/articles/PMC8795562/ /pubmed/35074915 http://dx.doi.org/10.1073/pnas.2116091119 Text en Copyright © 2022 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
Javed, Khayam
Jullien, Jerome
Agarwal, Gaurav
Lawrence, Nicola
Butler, Richard
Ioannou, Pantelis Savvas
Nazir, Farhat
Gurdon, J. B.
DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title_full DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title_fullStr DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title_full_unstemmed DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title_short DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
title_sort dna-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795562/
https://www.ncbi.nlm.nih.gov/pubmed/35074915
http://dx.doi.org/10.1073/pnas.2116091119
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