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The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but i...

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Autores principales: Irwin, RE, Scullion, C, Thursby, SJ, Sun, M, Thakur, A, Hilman, L, Callaghan, B, Thompson, PD, McKenna, DJ, Rothbart, SB, Xu, Guoliang, Walsh, CP
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10228402/
https://www.ncbi.nlm.nih.gov/pubmed/37246786
http://dx.doi.org/10.1080/15592294.2023.2216005
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author Irwin, RE
Scullion, C
Thursby, SJ
Sun, M
Thakur, A
Hilman, L
Callaghan, B
Thompson, PD
McKenna, DJ
Rothbart, SB
Xu, Guoliang
Walsh, CP
author_facet Irwin, RE
Scullion, C
Thursby, SJ
Sun, M
Thakur, A
Hilman, L
Callaghan, B
Thompson, PD
McKenna, DJ
Rothbart, SB
Xu, Guoliang
Walsh, CP
author_sort Irwin, RE
collection PubMed
description While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but its primary function in humans has been unclear. To determine what that was, we first established stable UHRF1 knockdowns (KD) in normal, immortalized human fibroblasts using targeting shRNA, since CRISPR knockouts (KO) were lethal. Although these showed a loss of DNA methylation across the whole genome, transcriptional changes were dominated by the activation of genes involved in innate immune signalling, consistent with the presence of viral RNA from retrotransposable elements (REs). We confirmed using mechanistic approaches that 1) REs were demethylated and transcriptionally activated; 2) this was accompanied by activation of interferons and interferon-stimulated genes and 3) the pathway was conserved across other adult cell types. Restoring UHRF1 in either transient or stable KD systems could abrogate RE reactivation and the interferon response. Notably, UHRF1 itself could also re-impose RE suppression independent of DNA methylation, but not if the protein contained point mutations affecting histone 3 with trimethylated lysine 9 (H3K9me3) binding. Our results therefore show for the first time that UHRF1 can act as a key regulator of retrotransposon silencing independent of DNA methylation.
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spelling pubmed-102284022023-05-31 The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells Irwin, RE Scullion, C Thursby, SJ Sun, M Thakur, A Hilman, L Callaghan, B Thompson, PD McKenna, DJ Rothbart, SB Xu, Guoliang Walsh, CP Epigenetics Research Paper While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but its primary function in humans has been unclear. To determine what that was, we first established stable UHRF1 knockdowns (KD) in normal, immortalized human fibroblasts using targeting shRNA, since CRISPR knockouts (KO) were lethal. Although these showed a loss of DNA methylation across the whole genome, transcriptional changes were dominated by the activation of genes involved in innate immune signalling, consistent with the presence of viral RNA from retrotransposable elements (REs). We confirmed using mechanistic approaches that 1) REs were demethylated and transcriptionally activated; 2) this was accompanied by activation of interferons and interferon-stimulated genes and 3) the pathway was conserved across other adult cell types. Restoring UHRF1 in either transient or stable KD systems could abrogate RE reactivation and the interferon response. Notably, UHRF1 itself could also re-impose RE suppression independent of DNA methylation, but not if the protein contained point mutations affecting histone 3 with trimethylated lysine 9 (H3K9me3) binding. Our results therefore show for the first time that UHRF1 can act as a key regulator of retrotransposon silencing independent of DNA methylation. Taylor & Francis 2023-05-29 /pmc/articles/PMC10228402/ /pubmed/37246786 http://dx.doi.org/10.1080/15592294.2023.2216005 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
spellingShingle Research Paper
Irwin, RE
Scullion, C
Thursby, SJ
Sun, M
Thakur, A
Hilman, L
Callaghan, B
Thompson, PD
McKenna, DJ
Rothbart, SB
Xu, Guoliang
Walsh, CP
The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title_full The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title_fullStr The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title_full_unstemmed The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title_short The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells
title_sort uhrf1 protein is a key regulator of retrotransposable elements and innate immune response to viral rna in human cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10228402/
https://www.ncbi.nlm.nih.gov/pubmed/37246786
http://dx.doi.org/10.1080/15592294.2023.2216005
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